DE60314639T2 - Fused Heteroaryl Derivatives for Use as P38 Kinase Inhibitors for the Treatment of U. RHEUMATIC ARTHRITIS - Google Patents

Abstract

Compounds of formula (I): wherein A is a 5-membered heteroaryl ring are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38, such as rheumatoid arthritis.

Description

These Invention relates to novel compounds and their use as pharmaceuticals, in particular as p38 kinase inhibitors for the treatment of conditions or Disease states by p38 kinase activity or by cytokines produced by the activity of p38 kinase will be taught. A number of p38 kinase inhibitors are already known, see for example Expert Opinion to Therapeutic Patents 2000, 10 (1) 25-37.

We have now identified a group of new compounds called inhibitors p38 kinase.

worin:
A ein kondensierter Heteroarylring mit 5 Gliedern ist, der gegebenenfalls mit bis zu zwei Substituenten substituiert ist, die unabhängig ausgewählt sind aus C_1-6-Alkyl, -(CH₂)_m-C_3-7-Cycloalkyl, Halogen, Cyano, Trifluormethyl, -(CH₂)_mOR³, -(CH₂)_mCO₂R³, -(CH₂)_mNR³R⁴, -(CH₂)_mCONR³R⁴, -(CH₂)_mNHCOR³, -(CH₂)_mSO₂NR³R⁴, -(CH₂)_mNHSO₂R³, -(CH₂)_mSO₂(CH₂)_nR⁵, einem Heterocyclylring mit 5 oder 6 Gliedern, der Stickstoff enthält, der gegebenenfalls mit C_1-2-Alkyl oder -(CH₂)_mCO₂R³ substituiert ist, und einem Heteroarylring mit 5 Gliedern, der gegebenenfalls mit C_1-2-Alkyl substituiert ist;
R¹ ausgewählt ist aus Methyl und Chlor;
R² ausgewählt ist aus -NH-CO-R⁶ und -CO-NH-(CH₂)_q-R⁷;
R³ ausgewählt ist aus Wasserstoff, C_1-6-Alkyl, das gegebenenfalls mit bis zu zwei OH-Gruppen substituiert ist, -(CH₂)_m-C_3-7-Cycloalkyl, -(CH₂)_mPhenyl, das gegebenenfalls mit R⁸ und/oder R⁹ substituiert ist, und -(CH₂)_mHeteroaryl, das gegebenenfalls mit R⁸ und/oder R⁹ substituiert ist;
R⁴ ausgewählt ist aus Wasserstoff und C_1-6-Alkyl, oder
R³ und R⁴ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclylring mit 5 oder 6 Gliedern bilden, der gegebenenfalls ein zusätzliches Heteroatom enthält, das aus Sauerstoff, Schwefel und N-R¹⁰ ausgewählt ist;
R⁵ ausgewählt ist aus C_1-6-Alkyl, das gegebenenfalls mit bis zu drei Halogenatomen substituiert ist, C_2-6-Alkenyl, das gegebenenfalls mit Phenyl substituiert ist, C_3-7-Cycloalkyl, Heteroaryl, das gegebenenfalls mit bis zu drei R⁸- und/oder R⁹-Gruppen substituiert ist, und Phenyl, das gegebenenfalls mit R⁸ und/oder R⁹ substituiert ist;
R⁶ ausgewählt ist aus Wasserstoff, C_1-6-Alkyl, -(CH₂)_q-C_3-7-Cycloalkyl, Trifluormethyl, -(CH₂)_rHeteroaryl, das gegebenenfalls mit R¹¹ und/oder R¹² substituiert ist, und -(CH₂)_rPhenyl, das gegebenenfalls mit R¹¹ und/oder R¹² substituiert ist;
R⁷ ausgewählt ist aus Wasserstoff, C_1-6-Alkyl, C_3-7-Cycloalkyl, -CONHR¹³, Phenyl, das gegebenenfalls mit R¹¹ und/oder R¹² substituiert ist, und Heteroaryl, das gegebenenfalls mit R¹¹ und/oder R¹² substituiert ist;
R⁸ und R⁹ jeweils unabhängig ausgewählt sind aus Halogen, Cyano, Trifluormethyl, Nitro, C_1-6-Alkyl, C_1-6-Alkoxy, -CONR¹³R¹⁴, -COR¹⁵, CO₂R¹⁵ und Heteroaryl, oder
R⁸ und R⁹ verknüpft sind, um einen kondensierten Heterocyclylring mit 5 Gliedern, der ein Heteroatom enthält, das ausgewählt ist aus Sauerstoff, Schwefel und N-R¹⁰, oder einen kondensierten Heteroarylring zu bilden;
R¹⁰ ausgewählt ist aus Wasserstoff und Methyl;
R¹¹ ausgewählt ist aus C_1-6-Alkyl, C_1-6-Alkoxy, -(CH₂)_q-C_3-7-Cycloalkyl, -CONR¹³R¹⁴, -NHCOR¹⁴, Halogen, CN, -(CH₂)_sNR¹⁶R¹⁷, Trifluormethyl, Phenyl, das gegebenenfalls mit einer oder mehreren R¹²-Gruppen substituiert ist, und Heteroaryl, das gegebenenfalls mit einer oder mehreren R¹²-Gruppen substituiert ist;
R¹² ausgewählt ist aus C_1-6-Alkyl, C_1-6-Alkoxy, Halogen, Trifluormethyl und -(CH₂)_sNR¹⁶R¹⁷;
R¹³ und R¹⁴ jeweils unabhängig ausgewählt sind aus Wasserstoff und C_1-6-Alkyl, oder
R¹³ und R¹⁴ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclylring mit 5 oder 6 Gliedern bilden, der gegebenenfalls ein zusätzliches Heteroatom enthält, das ausgewählt ist aus Sauerstoff, Schwefel und N-R¹⁰, worin der Ring mit bis zu zwei C_1-6-Alkyl-Gruppen substituiert sein kann;
R¹⁵ C_1-6-Alkyl ist;
R¹⁶ ausgewählt ist aus Wasserstoff, C_1-6-Alkyl und -(CH₂)_q-C_3-7-Cycloalkyl, das gegebenenfalls mit C_1-6-Alkyl substituiert ist; R¹⁷ ausgewählt ist aus Wasserstoff und C_1-6-Alkyl, oder
R¹⁶ und R¹⁷ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclylring mit 5 oder 6 Gliedern bilden, der gegebenenfalls ein zusätzliches Heteroatom enthält, das ausgewählt ist aus Sauerstoff, Schwefel und N-R¹⁰;
X und Y jeweils unabhängig ausgewählt sind aus Wasserstoff, Methyl und Halogen;
m ausgewählt ist aus 0, 1, 2 und 3;
n ausgewählt ist aus 0, 1, 2 und 3;
q ausgewählt ist aus 0, 1 und 2;
r ausgewählt ist aus 0 und 1; und
s ausgewählt ist aus 0, 1, 2 und 3.According to the invention, a compound of formula (I) is provided:

wherein:
A is a fused 5-membered heteroaryl ring optionally substituted with up to two substituents independently selected from C _1-6 alkyl, - (CH ₂ ) _m -C _3-7 cycloalkyl, halo, cyano, trifluoromethyl , - (CH ₂ ) _m OR ³ , - (CH ₂ ) _m CO ₂ R ³ , - (CH ₂ ) _m NR ³ R ⁴ , - (CH ₂ ) _m CONR ³ R ⁴ , - (CH ₂ ) _m NHCOR ³ , - (CH ₂ ) _m SO ₂ NR ³ R ⁴ , - (CH ₂ ) _m NHSO ₂ R ³ , - (CH ₂ ) _m SO ₂ (CH ₂ ) _n R ⁵ , a heterocyclyl ring having 5 or 6 members, which contains nitrogen optionally substituted with C _1-2 alkyl or - (CH ₂ ) _m CO ₂ R ³ , and a 5 membered heteroaryl ring optionally substituted with C _1-2 alkyl;
R ^{1 is} selected from methyl and chloro;
R ^{2 is} selected from -NH-CO-R ⁶ and -CO-NH- (CH ₂ ) _q -R ⁷ ;
R ^{3 is} selected from hydrogen, C _1-6 alkyl optionally substituted with up to two OH groups, - (CH ₂ ) _m -C _3-7 cycloalkyl, - (CH ₂ ) _m phenyl optionally substituted with R ⁸ and / or R ⁹ , and - (CH ₂ ) _m heteroaryl, which is optionally substituted with R ⁸ and / or R ⁹ ;
R ^{4 is} selected from hydrogen and C _1-6 alkyl, or
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclyl ring optionally containing an additional heteroatom selected from oxygen, sulfur and NR ¹⁰ ;
R ^{5 is} selected from C _1-6 alkyl optionally substituted with up to three halogen atoms, C _2-6 alkenyl optionally substituted with phenyl, C _3-7 cycloalkyl, heteroaryl optionally substituted with up to three R ⁸ and / or R ⁹ groups is substituted, and phenyl which is optionally substituted with R ⁸ and / or R ⁹ ;
R ^{6 is} selected from hydrogen, C _1-6 alkyl, - (CH ₂ ) _q -C _3-7 cycloalkyl, trifluoromethyl, - (CH ₂ ) _r heteroaryl optionally substituted with R ¹¹ and / or R ¹² and - (CH ₂ ) _r phenyl optionally substituted with R ¹¹ and / or R ¹² ;
R ^{7 is} selected from hydrogen, C _1-6 -alkyl, C _3-7 -cycloalkyl, -CONHR ¹³ , phenyl optionally substituted with R ¹¹ and / or R ¹² , and heteroaryl optionally substituted with R ¹¹ and / or R ^{12 is} substituted;
R ⁸ and R ^{9 are} each independently selected from halo, cyano, trifluoromethyl, nitro, C _1-6 alkyl, C _1-6 alkoxy, -CONR ¹³ R ¹⁴ , -COR ¹⁵ , CO ₂ R ¹⁵ and heteroaryl, or
R ⁸ and R ^{9 are} linked to form a fused 5-membered heterocyclyl ring containing a heteroatom selected from oxygen, sulfur and NR ¹⁰ , or a fused heteroaryl ring;
R ^{10 is} selected from hydrogen and methyl;
R ^{11 is} selected from C _1-6 alkyl, C _1-6 alkoxy, - (CH ₂ ) _q -C _3-7 cycloalkyl, -CONR ¹³ R ¹⁴ , -NHCOR ¹⁴ , halo, CN, - (CH ₂ ) _s NR ¹⁶ R ¹⁷ , trifluoromethyl, phenyl optionally substituted with one or more R ¹² groups, and heteroaryl optionally substituted with one or more R ¹² groups;
R ^{12 is} selected from C _1-6 alkyl, C _1-6 alkoxy, halo, trifluoromethyl and - (CH ₂ ) _s NR ¹⁶ R ¹⁷ ;
R ¹³ and R ^{14 are} each independently selected from hydrogen and C _1-6 alkyl, or
R ¹³ and R ^14, together with the nitrogen atom to which they are attached, form a 5 or 6 membered heterocyclyl ring optionally containing an additional heteroatom selected from oxygen, sulfur and NR ¹⁰ , wherein the ring contains up to two C _1-6 alkyl groups may be substituted;
R ^{15 is} C _1-6 alkyl;
R ^{16 is} selected from hydrogen, C _1-6 alkyl and - (CH ₂ ) _q -C _3-7 cycloalkyl optionally substituted with C _1-6 alkyl; R ^{17 is} selected from hydrogen and C _1-6 alkyl, or
R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclyl ring optionally containing an additional heteroatom selected from oxygen, sulfur and NR ¹⁰ ;
X and Y are each independently selected from hydrogen, methyl and halogen;
m is selected from 0, 1, 2 and 3;
n is selected from 0, 1, 2 and 3;
q is selected from 0, 1 and 2;
r is selected from 0 and 1; and
s is selected from 0, 1, 2 and 3.

worin:
A ein kondensierter Heteroarylring mit 5 Gliedern ist, der gegebenenfalls mit bis zu zwei Substituenten substituiert ist, die unabhängig ausgewählt sind aus C_1-6-Alkyl, -(CH₂)_m-C_3-7-Cycloalkyl, Halogen, Cyano, Trifluormethyl, -(CH₂)_mOR³, -(CH₂)_mNR³R⁴, -(CH₂)_mCONR³R⁴, -(CH₂)_mNHCOR³, -(CH₂)_mSO₂NR³R⁴, -(CH₂)_mNHSO₂R³, -(CH₂)_mSO₂(CH₂)_nR⁵, einem Heterocyclylring mit 5 oder 6 Gliedern, der Stickstoff enthält, der gegebenenfalls mit C_1-2- Alkyl substituiert ist, und einem Heteroarylring mit 5 Gliedern, der gegebenenfalls mit C_1-2-Alkyl substituiert ist;
R¹ ausgewählt ist aus Methyl und Chlor;
R² ausgewählt ist aus -NH-CO-R⁶ und -CO-NH-(CH₂)_q-R⁷;
R³ ausgewählt ist aus Wasserstoff, C_1-6-Alkyl, das gegebenenfalls mit bis zu zwei OH-Gruppen substituiert ist, -(CH₂)_m-C_3-7-Cycloalkyl, -(CH₂)_mPhenyl, das gegebenenfalls mit R⁸ und/oder R⁹ substituiert ist, und -(CH₂)_mHeteroaryl, das gegebenenfalls mit R⁸ und/oder R⁹ substituiert ist;
R⁴ ausgewählt ist aus Wasserstoff und C_1-6-Alkyl, oder
R³ und R⁴ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclylring mit 5 oder 6 Gliedern bilden, der gegebenenfalls ein zusätzliches Heteroatom enthält, das ausgewählt ist aus Sauerstoff, Schwefel und N-R¹⁰;
R⁵ ausgewählt ist aus C_1-6-Alkyl, C_3-7-Cycloalkyl, Heteroaryl, das gegebenenfalls mit R⁸ und/oder R⁹ substituiert ist, und Phenyl, das gegebenenfalls mit R⁸ und/oder R⁹ substituiert ist;
R⁶ ausgewählt ist aus Wasserstoff, C_1-6-Alkyl, -(CH₂)_q-C_3-7-Cycloalkyl, Trifluormethyl, -(CH₂)_rHeteroaryl, das gegebenenfalls mit R¹¹ und/oder R¹² substituiert ist, und -(CH₂)_rPhenyl, das gegebenenfalls mit R¹¹ und/oder R¹² substituiert ist;
R⁷ ausgewählt ist aus Wasserstoff, C_1-6-Alkyl, C_3-7-Cycloalkyl, CONHR¹³, Phenyl, das gegebenenfalls mit R¹¹ und/oder R¹² substituiert ist, und Heteroaryl, das gegebenenfalls mit R¹¹ und/oder R¹² substituiert ist;
R⁸ und R⁹ jeweils unabhängig ausgewählt sind aus Halogen, Cyano, Trifluormethyl, C_1-6-Alkyl, C_1-6-Alkoxy, COR¹⁵, CO₂R¹⁵ und Heteroaryl, oder
R⁸ und R⁹ verknüpft sind, um einen kondensierten Heterocyclylring mit 5 Gliedern zu bilden, der ein Heteroatom enthält, das ausgewählt ist aus Sauerstoff, Schwefel und N-R¹⁰;
R¹⁰ ausgewählt ist aus Wasserstoff und Methyl;
R¹¹ ausgewählt ist aus C_1-6-Alkyl, C_1-6-Alkoxy, -(CH₂)_q-C_3-7 ^- Cycloalkyl, -CONR¹³R¹⁴, -NHCOR¹⁴, Halogen, CN, -(CH₂)_sNR¹⁶R¹⁷, Trifluormethyl, Phenyl, das gegebenenfalls mit einer oder mehreren R¹²-Gruppen substituiert ist, und Heteroaryl, das gegebenenfalls mit einer oder mehreren R¹²-Gruppen substituiert ist;
R¹² ausgewählt ist aus C_1-6-Alkyl, C_1-6-Alkoxy, Halogen, Trifluormethyl und -(CH₂)_sNR¹⁶R¹⁷;
R¹³ und R¹⁴ jeweils unabhängig ausgewählt sind aus Wasserstoff und C_1-6-Alkyl, oder
R¹³ und R¹⁴ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclylring mit 5 oder 6 Gliedern bilden, der gegebenenfalls ein zusätzliches Heteroatom enthält, das ausgewählt ist aus Sauerstoff, Schwefel und N-R¹⁰, worin der Ring mit bis zu zwei C_1-6-Alkyl-Gruppen substituiert sein kann;
R¹⁵ C_1-6-Alkyl ist;
R¹⁶ ausgewählt ist aus Wasserstoff, C_1-6-Alkyl und -(CH₂)_q-C_3-7-Cycloalkyl, das gegebenenfalls mit C_1-6-Alkyl substituiert ist,
R¹⁷ ausgewählt ist aus Wasserstoff und C_1-6-Alkyl, oder
R¹⁶ und R¹⁷ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Heterocyclylring mit 5 oder 6 Gliedern bilden, der gegebenenfalls ein zusätzliches Heteroatom enthält, das ausgewählt ist aus Sauerstoff, Schwefel und N-R¹⁰;
m ausgewählt ist aus 0, 1, 2 und 3;
n ausgewählt ist aus 0, 1, 2 und 3;
q ausgewählt ist aus 0, 1 und 2;
r ausgewählt ist aus 0 und 1; und
s ausgewählt ist aus 0, 1, 2 und 3;
Repräsentative Beispiele für A schließen kondensierte Heteroaryl-Ringe mit 5 Gliedern ein, die bis zu zwei Heteroatome enthalten, die unabhängig ausgewählt sind aus Sauerstoff, Stickstoff und Schwefel. Bevorzugte kondensierte Heteroaryl-Ringe mit 5 Gliedern schließen Ringe ein, die bis zu zwei Heteroatome enthalten, die unabhängig ausgewählt sind aus Sauerstoff und Stickstoff, insbesondere Ringe, die zwei Heteroatome enthalten, die ausgewählt sind aus Sauerstoff und Stickstoff, wie zum Beispiel Ringe, die ein Stickstoffatom und ein zusätzliches Heteroatom enthalten, das ausgewählt ist aus Sauerstoff und Stickstoff.According to a further embodiment of the invention, a compound of the formula (IA) is provided:

wherein:
A is a fused 5-membered heteroaryl ring optionally substituted with up to two substituents independently selected from C _1-6 alkyl, - (CH ₂ ) _m -C _3-7 cycloalkyl, halo, cyano, trifluoromethyl , - (CH ₂ ) _m OR ³ , - (CH ₂ ) _m NR ³ R ⁴ , - (CH ₂ ) _m CONR ³ R ⁴ , - (CH ₂ ) _m NHCOR ³ , - (CH ₂ ) _m SO ₂ NO ³ R ⁴ , - (CH ₂ ) _m NHSO ₂ R ³ , - (CH ₂ ) _m SO ₂ (CH ₂ ) _n R ⁵ , a 5 or 6 membered heterocyclyl ring containing nitrogen optionally substituted with C _1-2 - alkyl is substituted, and a heteroaryl ring with 5 members, which is optionally substituted with C _1-2 alkyl;
R ^{1 is} selected from methyl and chloro;
R ^{2 is} selected from -NH-CO-R ⁶ and -CO-NH- (CH ₂ ) _q -R ⁷ ;
R ^{3 is} selected from hydrogen, C _1-6 alkyl optionally substituted with up to two OH groups, - (CH ₂ ) _m -C _3-7 cycloalkyl, - (CH ₂ ) _m phenyl optionally substituted with R ⁸ and / or R ⁹ , and - (CH ₂ ) _m heteroaryl, which is optionally substituted with R ⁸ and / or R ⁹ ;
R ^{4 is} selected from hydrogen and C _1-6 alkyl, or
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclyl ring optionally containing an additional heteroatom selected from oxygen, sulfur and NR ¹⁰ ;
R ^{5 is} selected from C _1-6 alkyl, C _3-7 cycloalkyl, heteroaryl optionally substituted with R ⁸ and / or R ⁹ , and phenyl optionally substituted with R ⁸ and / or R ⁹ ;
R ^{6 is} selected from hydrogen, C _1-6 alkyl, - (CH ₂ ) _q -C _3-7 cycloalkyl, trifluoromethyl, - (CH ₂ ) _r heteroaryl optionally substituted with R ¹¹ and / or R ¹² and - (CH ₂ ) _r phenyl optionally substituted with R ¹¹ and / or R ¹² ;
R ^{7 is} selected from hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, CONHR ¹³ , phenyl optionally substituted with R ¹¹ and / or R ¹² , and heteroaryl optionally substituted with R ¹¹ and / or R ^{12 is} substituted;
R ⁸ and R ^{9 are} each independently selected from halo, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, COR ¹⁵ , CO ₂ R ¹⁵ and heteroaryl, or
R ⁸ and R ^{9 are} linked to form a fused 5-membered heterocyclyl ring containing a heteroatom selected from oxygen, sulfur and NR ¹⁰ ;
R ^{10 is} selected from hydrogen and methyl;
R ¹¹ is selected from C _1-6 alkyl, C _1-6 alkoxy, - (CH _{2) q} -C _3-7 ^- cycloalkyl, -CONR ¹³ R ^14, -NHCOR ^14, halogen, CN, - (CH ₂ ) _s NR ¹⁶ R ¹⁷ , trifluoromethyl, phenyl optionally substituted with one or more R ¹² groups and heteroaryl optionally substituted with one or more R ¹² groups;
R ^{12 is} selected from C _1-6 alkyl, C _1-6 alkoxy, halo, trifluoromethyl and - (CH ₂ ) _s NR ¹⁶ R ¹⁷ ;
R ¹³ and R ^{14 are} each independently selected from hydrogen and C _1-6 alkyl, or
R ¹³ and R ^14, together with the nitrogen atom to which they are attached, form a 5 or 6 membered heterocyclyl ring optionally containing an additional heteroatom selected from oxygen, sulfur and NR ¹⁰ , wherein the ring contains up to two C _1-6 alkyl groups may be substituted;
R ^{15 is} C _1-6 alkyl;
R ^{16 is} selected from hydrogen, C _1-6 alkyl and - (CH ₂ ) _q -C _3-7 cycloalkyl optionally substituted with C _1-6 alkyl,
R ^{17 is} selected from hydrogen and C _1-6 alkyl, or
R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclyl ring optionally containing an additional heteroatom selected from oxygen, sulfur and NR ¹⁰ ;
m is selected from 0, 1, 2 and 3;
n is selected from 0, 1, 2 and 3;
q is selected from 0, 1 and 2;
r is selected from 0 and 1; and
s is selected from 0, 1, 2 and 3;
Representative examples of A include fused five membered heteroaryl rings containing up to two heteroatoms independently selected from oxygen, nitrogen and sulfur. Preferred fused 5-membered heteroaryl rings include rings containing up to two heteroatoms independently selected from oxygen and nitrogen, especially rings containing two heteroatoms selected from oxygen and nitrogen, such as rings contain a nitrogen atom and an additional heteroatom selected from oxygen and nitrogen.

In one embodiment, A is selected from fused pyrazolyl and isoxazolyl rings, such as those shown below:

In another embodiment, A is selected from fused pyrrolyl and thiazolyl rings, such as those shown below:

Of the Ring A may optionally be substituted with up to two substituents which are located at every position of the ring. Preferably Ring A is substituted with a substituent.

In one embodiment, A is optionally substituted with up to two substituents independently selected from C _1-6 alkyl, - (CH ₂ ) _m -C _3-7 cycloalkyl, halo, cyano, trifluoromethyl, - (CH ₂ ) _m OR ³ , - (CH ₂ ) _m NR ³ R ⁴ , - (CH ₂ ) _m CONR ³ R ⁴ , - (CH ₂ ) _m NHCOR ³ , - (CH ₂ ) _m SO ₂ NR ³ R ⁴ , - ( CH ₂ ) _m NHSO ₂ R ³ , - (CH ₂ ) _m SO ₂ (CH ₂ ) _n R ⁵ , a 5 or 6 membered heterocyclyl ring containing a nitrogen optionally substituted with C _1-2 alkyl and a 5-membered heteroaryl ring optionally substituted with C _1-2 alkyl.

Representative examples of substituents for A include ^C _1-4 ^- alkyl, in particular methyl - (CH _{2) m} -C _3-7 cycloalkyl, in particular - (CH _{2) m-cyclopropyl;} - (CH ₂ ) _m CO ₂ R ³ ; - (CH ₂ ) _m NR ³ R ⁴ ; - (CH ₂ ) _m CONR ³ R ⁴ ; - (CH ₂ ) _m NHCOR ³ ; - (CH ₂ ) _m SO ₂ (CH ₂ ) _n R ⁵ ; and a 5 or 6 membered heterocyclyl ring containing nitrogen, especially 4-piperidinyl optionally substituted with C _1-2 alkyl or - (CH ₂ ) _m CO ₂ R ³ .

Typical substituents for A include C _1-4 alkyl, especially methyl, - (CH ₂ ) _m OR ³ , - (CH ₂ ) _m NR ³ R ⁴ , - (CH ₂ ) _m SO ₂ (CH ₂ ) _n R ⁵ and a 5 or 6 membered heterocyclyl ring containing nitrogen, especially piperazinyl and piperidinyl, such as 4-piperidinyl.

A representative example of R ¹ is methyl. In one embodiment, R ^{2 is} -CO-NH- (CH ₂ ) _q -R ⁷ . Representative examples of R ³ include hydrogen; C _1-6 alkyl, which is optionally substituted with up to two OH group, in particular methyl, ethyl, n-propyl, isopropyl, t-butyl or 2,2-dimethylpropyl, optionally substituted with up to two OH groups are; - (CH ₂ ) _m -C _3-7 cycloalkyl, in particular - (CH ₂ ) _m cyclopropyl; - (CH ₂ ) _m -phenyl, which is optionally substituted by R ⁸ and / or R ⁹ ; and - (CH ₂ ) _m heteroaryl, especially thiazolyl optionally substituted with R ⁸ and / or R ⁹ .

Other representative examples of R ³ include hydrogen and C _1-4 alkyl substituted with up to two OH groups, especially 1,3-dihydroxyprop-2-yl.

Representative examples of R ⁴ include hydrogen and C _1-4 alkyl, such as methyl. In particular, a representative example of R ^{4 is} hydrogen.

In one embodiment, R ³ and R ⁴ together with the nitrogen to which they are attached form a 5 or 6 membered heterocyclyl ring optionally containing an additional heteroatom selected from oxygen, sulfur and NR ¹⁰ , especially one Pyrrolidinyl, piperidinyl, piperazinyl or 4-methylpiperazinyl or morpholinyl ring.

In one embodiment, R ^{5 is} selected from C _1-6 alkyl, C _3-7 cycloalkyl, heteroaryl optionally substituted with R ⁸ and / or R ⁹ , and phenyl optionally substituted with R ⁸ and / or R ⁹ is substituted.

Representative examples of R ⁵ include C _1-6 alkyl which is optionally substituted with up to three halogen atoms, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl and n-hexyl which are substituted with up to three halogen atoms ; C _2-6 alkenyl optionally substituted with phenyl, especially ethenyl, optionally substituted with phenyl; C _3-7 cycloalkyl, especially cyclopropyl; Heteroaryl, which is optionally substituted with R ⁸ and / or R ⁹ , in particular a heteroaryl ring with 5 members, which contains at least one heteroatom selected from oxygen, nitrogen and sulfur, such as furyl, thienyl, isoxazolyl, imidazolyl or pyrazolyl optionally substituted with up to three R ⁸ and / or R ⁹ groups; and phenyl optionally substituted with R ⁸ and / or R ⁹ .

Other representative examples of R ⁵ include C _1-4 alkyl, especially methyl, phenyl optionally substituted with R ⁸ and / or R ⁹ , and a 5 member heteroaryl ring containing at least one heteroatom selected is from oxygen, nitrogen and sulfur, which is optionally substituted with R ⁸ and / or R ⁹ , in particular thienyl, which is optionally substituted with R ⁸ and / or R ⁹ .

Representative examples of R ⁶ include - (CH ₂ ) _r heteroaryl optionally substituted with R ¹¹ and / or R ¹² , especially in a heteroaryl of 5 or 6 members containing at least one heteroatom selected from Oxygen, nitrogen and sulfur, for example pyridinyl optionally substituted with - (CH ₂ ) _s NR ¹⁶ R ¹⁷ , furyl or thienyl.

Representative examples of R ⁷ include C _3-7 cycloalkyl, phenyl optionally substituted with R ¹¹ and / or R ¹² , and heteroaryl optionally substituted with R ¹¹ and / or R ¹² . In one embodiment, R ^{7 is} selected from C _3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopropyl; Phenyl which is optionally substituted by C _1-4 alkoxy, in particular methoxy, or - (CH ₂ ) _s NR ¹⁶ R ¹⁷ ; and a heteroaryl optionally substituted with R ¹¹ and / or R ¹² , in particular a heteroaryl of 5 or 6 members containing at least one heteroatom selected from oxygen, nitrogen and sulfur, for example pyridinyl, thiazolyl or thiadiazolyl. In a further embodiment, R ^{7 is} C _3-6 -cycloalkyl, in particular cyclopropyl.

In one embodiment, R ⁸ and R ^{9 are} each independently selected from halogen, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, -COR ¹⁵ , -CO ₂ R ¹⁵ and heteroaryl.

Representative examples of R ⁸ and R ⁹ include halogen, especially chlorine and fluorine; cyano; trifluoromethyl; nitro; C _1-4 alkyl, in particular methyl, ethyl, n-propyl, isopropyl or n-butyl; C _1-4 alkoxy, especially methoxy; -CONR ¹³ R ¹⁴ ; -COR ¹⁵ ; -CO ₂ R ¹⁵ and heteroaryl, in particular a 5-membered heteroaryl ring containing up to two heteroatoms independently selected from nitrogen and oxygen oxygen, for example isoxazolyl.

Other representative examples of R ⁸ and R ⁹ include halogen, especially fluoro, cyano, trifluoromethyl, C _1-4 alkoxy, especially methoxy, COR ¹⁵ , CO ₂ R ¹⁵ and heteroaryl, in particular a 5 membered heteroaryl ring contains up to two heteroatoms independently selected from nitrogen and oxygen, for example isoxazolyl.

In another embodiment, R ⁸ and R ^{9 are} linked to form a fused 5-membered heterocyclyl ring containing a heteroatom selected from oxygen, sulfur, and NR ¹⁰ .

Representative examples include R ⁸ and R ⁹ linked to form a condensed heterocyclyl 5-membered ring containing oxygen or a fused 5-membered heteroaryl ring containing up to 3 heteroatoms selected are made of oxygen and nitrogen.

Another representative example is where R ⁸ and R ^{9 are} linked to form a fused five-membered heterocyclyl ring containing oxygen.

Representative examples of R ¹¹ and R ¹² include C _1-4 alkoxy, especially methoxy, and - (CH ₂ ) _s NR ¹⁶ R ¹⁷ .

Representative examples of R ¹³ and R ¹⁴ include hydrogen and C _1-4 alkyl, especially hydrogen and methyl.

Representative examples of R ¹⁵ include C _1-4 alkyl, especially methyl.

In one embodiment, R ¹⁶ and R ¹⁷ together with nitrogen to which they are attached form a 5 or 6 membered heterocyclyl ring optionally further containing an additional oxygen atom, especially pyrrolidinyl or morpholino.

In an embodiment X and Y are each independent selected from hydrogen, chlorine and fluorine. Representative examples of X include hydrogen and fluorine. A representative example for Y is hydrogen. In another embodiment, X and Y are each Hydrogen.

In an embodiment m is selected from 0, 1 and 2, in particular 0 and 1.

Representative examples for Close 0, 1 and 2. Further representative examples for Close 0 and 1 on.

Representative examples for Close q 0 and 1 on, in particular 0.

One representative example for r is 0.

One representative example for s is 0.

It is to be understood that the present invention includes all combinations of particular and preferred groups described above. It is also to be understood that the present invention encompasses compounds of the formula (I) wherein a particular group or parameter, for example R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁶ , R ¹⁷ , m, q or s can occur more than once. In such compounds, it will be understood that each group or parameter is independently selected from the listed values.

Particular compounds of the invention include those mentioned in the examples. Specific examples that may be mentioned include the following:
N- [4-Methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) phenyl] -2-pyrrolidin-1-ylisonicotinamid,
N-cyclopropyl-4-methyl-3- [1- (phenylsulfonyl) -1H-indazol-5-yl] benzamide,
N-cyclopropyl-3- {1 - [(3-fluorophenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide,
N-cyclopropyl-4-methyl-3- [1- (methylsulfonyl) -1H-indazol-5-yl] benzamide,
N-cyclopropyl-3- {1 - [(4-fluorophenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide,
N-cyclopropyl-4-methyl-3- [3- (4-morpholinyl) -1,2-benzisoxazol-6-yl] benzamide,
N-cyclopropyl-4-methyl-3- {3- [(1,3-thiazol-2-ylamino) ethyl 2-oxo-2-] -1,2-benzisoxazol-6-yl} benzamide,
N-cyclopropyl-4-methyl-3- [3- (4-morpholinylmethyl) -1,2-benzisoxazol-6-yl] benzamide,
N-cyclopropyl-4-methyl-3- [3- (1-pyrrolidinylmethyl) -1,2-benzisoxazol-6-yl] benzamide,
N-cyclopropyl-4-methyl-3- {1 - [(1-methylethyl) sulfonyl] -1H-indazol-5-yl} -benzamide,
N-cyclopropyl-3- [1- (ethylsulfonyl) -1H-indazol-5-yl] -4-methylbenzamide, N-cyclopropyl-3- [1- (cyclopropylsulfonyl) -1H-indazol-5-yl] -4- methylbenzamide,
N-cyclopropyl-4-methyl-3- [1- (2-thienylsulfonyl) -1H-indazol-5-yl] benzamide,
3- {1 - [(2-cyanophenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-4-methylbenzamide,
N-cyclopropyl-3-fluoro-4-methyl-5- [1- (2-thienylsulfonyl) -1H-indazol-5-yl] benzamide,
N-cyclopropyl-3-fluoro-4-methyl-5- [1- (3-thienylsulfonyl) -1H-indazol-5-yl] benzamide,
N-cyclopropyl-3-fluoro-4-methyl-5- {1 - [(1-methylethyl) sulfonyl] -1H-indazol-5-yl} -benzamide,
N-cyclopropyl-3-fluoro-4-methyl-5- [1- (propylsulfonyl) -1H-indazol-5-yl] benzamide,
N-cyclopropyl-3-fluoro-4-methyl-5- [1- (methylsulfonyl) -1H-indazol-5-yl] benzamide,
3- [1- (butylsulfonyl) -1H-indazol-5-yl] -N-cyclopropyl-5-fluoro-4-methylbenzamide,
N-cyclopropyl-3- [1- (cyclopropylsulfonyl) -1H-indazol-5-yl] -5-fluoro-4-methylbenzamide,
3- {1 - [(5-chloro-2-thienyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide,
N-cyclopropyl-3- {1 - [(3,5-dimethyl-4-isoxazolyl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide,
N-cyclopropyl-3- [1- (ethylsulfonyl) -1H-indazol-5-yl] -5-fluoro-4-methylbenzamide,
3- {1 - [(2-chlorophenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide,
N-cyclopropyl-3-fluoro-4-methyl-5- {1 - [(2-methylphenyl) sulfonyl] -1H-indazol-5-yl} -benzamide,
N-cyclopropyl-3-fluoro-4-methyl-5- [1- (phenylsulfonyl) -1H-indazol-5-yl] benzamide,
N-cyclopropyl-3- {1 - [(2,5-difluorophenyl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide,
N-cyclopropyl-3-fluoro-5- {1 - [(2-fluorophenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide,
N-cyclopropyl-3- [1- (cyclopropylmethyl) -1H-indazol-5-yl] -4-methylbenzamide;
N-cyclopropyl-3-fluoro-4-methyl-5- [3-methyl-1- (2-thienylsulfonyl) -1H-indazol-5-yl] benzamide.

As used herein, the term "alkyl" refers to straight or branched chain hydrocarbon chains containing a specific number of carbon atoms. For example, C _1-6 alkyl means a straight or branched chain alkyl containing at least 1 and at most 6 carbon atoms. Examples of "alkyl" as used herein include, without limitation, methyl, ethyl, n -propyl, n -butyl, n -pentyl, isobutyl, isopropyl and t -butyl. A C _1-4 alkyl group is preferably, for example, methyl, ethyl, isopropyl or t-butyl. The alkyl groups may optionally be substituted with one or more fluorine atoms, for example trifluoromethyl.

As used herein, the term "alkenyl" refers to straight or branched chain hydrocarbon chains containing the specific number of carbon atoms and at least one double bond. For example, C _2-6 alkenyl means a straight or branched chain alkenyl containing at least 2 and at most 6 carbon atoms and at least one double bond. Examples of "alkenyl" as used herein include, without limitation, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-methylbut-2-enyl, 3-hexenyl and 1,1-dimethylbut-2-enyl.

As used herein, the term "alkoxy" refers to a straight chain or branched chain alkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy. A C _1-4 alkoxy group is preferably, for example, methoxy or ethoxy.

As used herein, the term "cycloalkyl" refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms, which may optionally contain up to one double bond. For example, C _3-7 cycloalkyl means a non-aromatic ring containing at least 3 and at most 7 ring carbon atoms. Examples of "cycloalkyl" as used herein include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A C _3-6 cycloalkyl group is preferably, for example, cyclopropyl, cyclopentyl or cyclohexyl.

As used herein, the terms "heteroaryl ring" and "heteroaryl", unless otherwise defined, refer to a monocyclic unsaturated hydrocarbon ring of 5 to 7 members containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, the heteroaryl ring has 5 or 6 ring atoms. Examples of heteroaryl rings include, without limitation, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. The ring may optionally be substituted with one or more substituents independently selected C _1-6 alkyl and oxy.

As used herein, the terms "heterocyclyl ring" or "heterocyclyl", unless otherwise defined, refers to a monocyclic saturated hydrocarbon ring of from 3 to 7 members containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, the heterocyclyl ring has 5 or 5 ring atoms. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, tetrahydrofuranyl and thiomorpholino. The ring may be optionally substituted with one or more substituents independently selected from ^C 1-6 ^- alkyl and oxy.

As As used herein, the terms "halogen" or "halo" refer to the elements fluorine, chlorine, bromine and iodine. Preferred halogens are Fluorine, chlorine and bromine. A particularly preferred halogen is fluorine or Chlorine.

As used herein, the term "solvate" refers to a complex of variable stoichiometry, the one solved by Substance (in this invention, a compound of formula (I) or Salt thereof) and a solvent is formed. Such for Solvents used for the purpose of the invention may include biological activity of the solved Do not disturb Stoffes. examples for suitable solvents shut down Water, methanol, ethanol and acetic acid. Preferably that is used solvents a pharmaceutically acceptable solvent. examples for suitable pharmaceutically acceptable solvents include water, Ethanol and acetic acid one. All such solvents are included within the scope of the present invention.

Certain Compounds of formula (I) can in stereoisomeric forms (e.g., they may have one or more asymmetric Contain carbon atoms or have cis-trans isomerism). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are within the scope of the present invention Invention included. The present invention also includes the individual isomers of the compounds represented by the formula (I), as mixtures with isomers thereof, wherein a or several chiral centers are inverted. In the same way its understandable, that compounds the Formula (I) in tautomeric forms other than those shown in the formula can exist and these are also within the scope of the present invention Invention included.

salts The compounds of the present invention are also of the scope the invention comprises, and can for example acid addition salts comprising the reaction of an acid with a basic nitrogen atom, which is present in a compound of formula (I), emerge.

salts the term "pharmaceutical acceptable salts "are included, refer to non-toxic salts of the compounds of this invention. Representative Close salts the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, Bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, Chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, Esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarananilate, Hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, Iodide, isethionate, lactate, lactobionate, laurate, Malst, Malest, Mandelate, Mesylate, methyl bromide, methyl nitrate, methyl sulfate, monopotassium maleate, Mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), Palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, Salicylate, sodium, stearate, subacetate, succinate, tannin, tartrate, Teoclate, tosylate, triethiodide, trimethylammonium and valerate. Other Salts that are not pharmaceutically acceptable may be useful in the preparation of the compounds of this invention, and these form another aspect of the invention.

The Compounds of this invention can by a variety of methods, including standard chemistry become. Any previously defined variable will be retained unless otherwise specified given their previously defined meaning. Illustrative general Synthetic methods are listed below, and specific compounds of the invention are then made in the working examples.

worin A wie zuvor definiert ist und Z¹ Halogen ist, insbesondere Brom, mit einer Verbindung der Formel (IIIA) oder (IIIB):

worin R¹, R², X und Y wie zuvor definiert sind, in Gegenwart eines Katalysators, zum Beispiel Tetrakis(triphenylphosphin)palladium, hergestellt werden.A compound of the formula (I) can be obtained by reacting a compound of the formula (II)

wherein A is as defined above and Z ^{1 is} halogen, in particular bromine, with a compound of the formula (IIIA) or (IIIB):

wherein R ¹ , R ² , X and Y are as defined above, in the presence of a catalyst, for example, tetrakis (triphenylphosphine) palladium.

worin R¹, R², X und Y wie zuvor definiert sind, und Z² Halogen ist, insbesondere Iod, mit Bis(pinnacolato)diboron, [1,1'-Bis(diphenylphosphino)ferrocen]-dichlorpalladium(II)-Komplex (PdCl₂(ppdf)) und Kaliumacetat in einem Lösungsmittel wie DMF hergestellt werden.A compound of the formula (IIIA) can be obtained by, for example, reacting a compound of the formula (IV)

wherein R ¹ , R ² , X and Y are as previously defined and Z ^{2 is} halogen, especially iodine, with bis (pinnacolato) diboron, [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) complex (PdCl ₂ (ppdf)) and potassium acetate in a solvent such as DMF.

A Compound of formula (IIIB) can be prepared by, for example, reacting a Compound of the formula (IV) as described above with n-butyllithium and triisopropyl borate in a solvent how THF are made.

worin R¹, X, Y und Z² wie zuvor definiert sind, mit einer Säureverbindung der Formel (VI) R₆CO₂H (VI)worin R⁶ wie zuvor definiert ist, unter Amid-bildenden Bedingungen hergestellt werden.When R ^{2 is} -NH-CO-R ⁶ , a compound of formula (IV) may be prepared by reacting an amine of formula (V)

wherein R ¹ , X, Y and Z ^{2 are} as defined above, with an acid compound of the formula (VI) R ₆ CO ₂ H (VI) wherein R ^{6 is} as previously defined under amide-forming conditions.

suitable Amide-forming conditions are known in the art and include the Add a base such as DIPEA to a mixture of the amine of the formula (V), the acid of formula (VI) and HATU in a solvent such as DMF.

worin R¹, X, Y und Z² wie zuvor definiert sind, durch Umwandlung der Säure in eine aktivierte Form der Säure, zum Beispiel das Säurechlorid, durch Behandlung mit zum Beispiel Thionylchlorid und dann Umsetzen der aktivierten Säure, wobei diese mit einer Amin-Verbindung der Formel (VIII) R²-(CH₂)_q-NH₂ (VIII)gebildet wird, worin R⁷ wie zuvor definiert ist, unter Amid-bildenden Bedingungen hergestellt werden.Alternatively, when R ^{2 is} -CO-NH- (CH ₂ ) _q -R ⁷ , a compound of formula (IV) may be readily prepared from a corresponding acid compound of formula (VII)

wherein R ¹ , X, Y and Z ^{2 are} as defined above, by conversion of the acid into an activated form of the acid, for example the acid chloride, by treatment with, for example, thionyl chloride and then reacting the activated acid, with an amine Compound of the formula (VIII) R ² - (CH ₂ ) _q -NH ₂ (VIII) wherein R ^{7 is} as previously defined are prepared under amide-forming conditions.

suitable Amide-forming conditions are well known and include that Treat a solution of Acid of Formula (VII) or the activated form thereof in, for example, DMF with an amine of formula (VIII) in the presence of a base such as Example triethylamine.

Wäßrige Base/Lösungsmittel Schema 1 For example, a general method for preparing the compounds of formula (I) comprises the reaction set forth in Scheme 1 below.

Aqueous base / solvent Scheme 1

alternative comprises another general method is an output stage modification of a Compound of formula (I) in another compound of formula (I). Suitable transformations of a functional group for the transformation a compound of formula (I) into another compound of formula (I) are known in the art and are for example Comprehesive Heterocyclic Chemistry II, ed. A.R. Katritzky, C.W. Rees and E.F.V. Scriven (Pergamon Press, 1996), Comprehensive Organic Functional Group Transformations, Ed. A.R. Katritzky, O. Meth-Cohn and C.W. Rees (Elsevier Science Ltd., Oxford, 1995), Comprehensive Organic Chemistry, Ed. D. Barton and W.D. Ollis (Pergamon Press, Oxford, 1979) and Comprehensive Organic Transformations, R.C. Larock (VCH Publishers Inc., New York, 1989).

Schema 2 For example, a method for preparing the compounds of formula (I) comprises the reactions set forth below in Scheme 2.

Scheme 2

Schema 3 For example, another method for preparing the compounds of formula (I) comprises the reactions set forth below in Scheme 3.

Scheme 3

Schema 4 For example, another method for preparing the compound of formula (I) comprises the reactions set forth below in Scheme 4.

Scheme 4

Schema 5 For example, another method for preparing the compounds of formula (I) comprises the reactions set forth below in Scheme 5.

Scheme 5

Schema 6 For example, another method for preparing the compounds of formula (I) comprises the reactions set forth below in Scheme 6.

Scheme 6

Schema 7 For example, another method of preparing the compounds of formula (I) comprises the reactions set forth below in Scheme 7.

Scheme 7

Schema 8 For example, another example of preparing the compound of formula (I) includes the reactions set forth below in Scheme 8

Scheme 8

Those skilled in the art will understand that in preparing the compounds of the invention, it may be necessary and / or desirable to protect one or more sensitive groups in the molecule to prevent undesired side reactions. Suitable protecting groups for use in accordance with the present invention are known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis", TW Greene and PGM Wuts (John Wiley & Sons 1991) or "Protecting Groups", PJ Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino-protecting groups include acyl-type protecting groups (eg, formyl, trifluoroacetyl, acetyl), aromatic urethane-type protecting groups (eg, benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urea than protecting groups (eg, 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl-type protecting groups (eg, benzyl, trityl, chlorotrityl). Examples of suitable oxygen protecting groups may include, for example, alkylsilyl groups such as trimethylsilyl or tert-butyldimethylsilyl; Alkyl ethers, such as tetrahydropyranyl or tert-butyl; or esters, such as acetate.

While it for the Compounds of the present invention is possible as the new chemical to be administered, the compounds of the formula (I) conveniently in the form of pharmaceutical compositions administered. Therefore, we present in another aspect of the invention a pharmaceutical composition which is a compound of formula (I) in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

The Compounds of formula (I) can for the Administration may be formulated in any suitable manner. You can to example for topical administration or for administration by inhalation or more preferably for formulated oral, transdermal or parenteral administration be. The pharmaceutical composition may be in a form so that you influence the controlled release of the compounds of formula (I) can. A particularly preferred method of administering, and the corresponding formulation is oral administration.

For the oral Administration may be in the form of the pharmaceutical composition and administered as, for example, tablets (including sublingual Tablets) and capsules (each including time-defined release and extended Release formulations), pills, powders, granules, elixirs, Tinctures, emulsions, solutions, Syrups or suspensions obtained by conventional means with acceptable Be prepared excipients.

To the example for oral administration may be in the form of a tablet or capsule the active ingredient component with an oral, non-toxic pharmaceutical acceptable inert carrier, such as ethanol, glycerin, water and the like. Combined. Powders become suitable by triturating the compound fine size and mixing with a similar one Melted pharmaceutical carrier, such as a edible Carbohydrate, such as starch or mannitol become. A flavoring, preservative, dispersant and Dye can also be present.

capsules can by preparing a powder mixture as described above and To fill in a molded gelatin tube getting produced. Lubricants and lubricants, such as colloidal Silica, talc, Magnesium stearate, calcium stearate or solid polyethylene glycol may be added the powder mixture before the filling process be added. An explosive or solubilizer, such as For example, agar-agar, calcium carbonate or sodium carbonate may also be used be added to the availability improve the drug when the capsule is taken.

Furthermore, if desired or necessary, suitable binders, lubricants, disintegrants and dyes may be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulated or whipped, adding a lubricating and disintegrating agent and compressing into tablets. A powder mix is prepared by mixing the compound, suitably minced, with a diluent or base as described above, and optionally with a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution retardant such as paraffin, a receiving accelerator, such as a quaternary salt, and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting with a binder, such as syrup, starch paste, Acadiaschleim or solutions of cellulose-based or polymeric materials, and forcing through a sieve. As an alternative to granulation, the powder mixture can be passed through the tabletting machine and the result is incompletely shaped blanks that are broken into granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet-forming press rams. The lubricated mixture is then compression molded into tablets. The compounds of the present invention may also be reacted with a free-flowing inert Carriers can be compressed and directly pressed into tablets without having to go through the granulation or push steps. A clear or opaque protective layer consisting of a sealed layer of shellac, a coating of sugar or polymeric material and a wax polishing coating may be provided. Dyes can be added to these coatings to distinguish different unit dosages.

oral Liquids, such as solutions, Syrups and elixirs can be prepared in dosage unit forms, so that a given Amount contains a predetermined amount of the compound. syrups can by dissolving of the compound in a suitably aromatized aqueous solution be while Elixirs through the use of a non-toxic alcoholic Vehicles are produced. Suspensions can be prepared by dispersing the Compound be formulated in a non-toxic vehicle. solubilizing agent and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives, for Example peppermint oil or saccharin, and the like also be added.

Where attached, can Dosage unit formulations for oral administration microencapsulated be. The formulation may also be used to extend or maintain release such as by coating or embedding of particulate Material in polymer, wax or the like. Be prepared.

The Compounds of the present invention may also be in the form of liposome delivery systems be administered, such as small unilamellar vesicles, size unilamellar vesicles and multilamellar vesicles. liposomes can from a variety of phospholipids, such as cholesterol, Stearylamine or phosphatidylcholines are formed.

The Compounds of the present invention may also be in the form of liposome emulsion delivery systems be administered, such as in the form of small unilamellar Vesicles, Great unilamellar vesicles and multilamellar vesicles. liposomes can from a variety of phospholipids, such as cholesterol, Stearylamine or phosphatidylcholines are formed.

links of the present invention also by the use of monoclonal antibodies as individual carriers, to the compound molecules knotted, be. The compounds of the present invention may also with soluble Polymer be linked as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, Pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylasparatamidophenol or polyethylene oxide polylysine substituted with palmitolyl residues is, include. About that can out the compounds of the present invention to a class of biodegradable Polymers that are useful in achieving a controlled release of a drug are, for example, polylactic acid, Polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, Polydihydropyrans, polycyanoacrylates and cross-linked or amiphipathic block copolymers or hydrogels.

The present invention includes pharmaceutical compositions containing 0.1 to 99.5%, in particular 0.5 to 90% of a compound of the formula (I) in combination with a pharmaceutically acceptable carrier.

In similar Way, the composition in nasal, ophthalmic, ear-related, rectal, topical, intravenous (both bolus and infusion), peritoneal, intra-articular, subcutaneous or intramuscular, Inhaled or insufflated form, everything Uses that are familiar to those skilled in the pharmaceutical field well known.

For the transdermal Administration may be in the form of the pharmaceutical composition a transdermal patch, such as a transdermal patch iontophoretic patch.

For parenteral administration, the pharmaceutical composition may be given as an injection or a continuous infusion (eg, intravenous, intravascular, or subcutaneous). The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain certain formulating agents such as suspending, stabilizing and / or disintegrating agents. For injection administration, they may take the form of a unit dose preparation or as a multi-dose preparation, preferably with an additional preservative. Alternatively, for parenteral administration, the active ingredient may be in powder form Reconstitution with a suitable vehicle.

The Compounds of the invention can also be formulated as a depot preparation. Such long-acting Formulations can by implantation (for example, subcutaneous or intramuscular) or by intramuscular Be administered injection. Therefore, for example, the compounds of the invention with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or Ion exchange resins or as sparingly soluble derivatives, for example as a limited soluble Salt, to be formulated.

alternative can the composition for a topical application, for example in the form of ointments, creams, Lotions, eye ointments, eye drops, ear drops, mouthwashes, impregnated associations and sutures and aerosols, and may be appropriate conventional additions included, including for example, preservatives, solvents, the drug penetration support, and softening agents in ointments and creams. Such topical formulations can also compatible conventional carriers, for example Cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers can from about 1 to about 98% by weight of the formulation, normally make up to about 80% by weight of the formulation.

For administration by inhalation the compounds according to the invention become pleasant in the form of an aerosol spray delivery of pressurized Parcels or a nebulizer supplied, with the use of a suitable propellant, e.g. Dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, Tetrafluoroethane, heptafluoropropane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol can the dosage unit by providing a valve for the supply of a measured quantity.

capsules and cartridges of e.g. Gelatin for use in an inhaler or insufflator can be formulated which are a powder mixture of a compound of the invention and a suitable powder base, such as lactose or starch.

The Pharmaceutical compositions are generally used in one Amount administered for the treatment or prophylaxis of a specific State or states is effective. An initial one Human dosage is controlled by clinical monitoring of symptoms such as Symptoms for the selected one Condition, accompanied. In general, the compositions in an amount of the active ingredient of at least about 100 μg / kg of body weight administered. In most cases they are in one or more doses in an amount that is about 20 mg / kg body weight does not exceed per day, administered. Preferably, the daily dose is in most make of about 100 μg / kg to about 5 mg / kg body weight. For the Administration to particular mammals, and in particular humans, it is expected that the daily dosage of the Active ingredient of from 0.1 mg / kg to 10 mg / kg and typically about 1 mg / kg is. It will be appreciated that the optimal dosage by Standard method for every treatment modality and indication, considering the indication, its severity, the route of administration, the complicating Conditions and the like. Be determined. The doctor will in any case Determine the actual dosage that is most suitable for an individual is and with the age, weight and answer of the corresponding Individual varies. The effectiveness of a selected actual For example, dose can be easily measured by measuring clinical symptoms or anti-inflammatory Standard indices for administering the selected dose. The above listed Dosages are exemplary for the average case. There may well be individual cases where higher or lower dose ranges are and are within the scope of this invention. For conditions and disease states that can be treated by the present invention, the retention consistent daily Quantities in a subject over an extended period of time, for example in a maintenance administration scheme, be particularly advantageous.

In In another aspect, the present invention provides a compound of formula (I) for use in therapy.

The Compounds of the present invention are generally inhibitors serine / threonine kinase p38 and are therefore also inhibitors cytokine production mediated by p38 kinase. Within the meaning of the term "inhibitors of the series / threonine kinase p38 "will be such Compounds included the ability of p38, a phosphate group of ATP on a protein substrate, as described below Test, transfer, disturb.

It will be understood that the compounds of the invention may be selective for one or more of the isoforms of p38, for example p38α, p38β, p38γ and / or p38δ. In one embodiment, the compounds of the invention selectively inhibit the p38α isoform. In another embodiment, the compounds of the invention selectively inhibit the p38β isoform. In a further embodiment, the compounds of the invention selectively inhibit the p38α and p38β isoforms. Assays for determining the selectivity of the compounds for the p38 isoforms are described, for example, in WO 99/61426 . WO 00/71535 and WO 02/46158 described.

It It is known that p38 kinase activity can be increased can (locally or over the entire body), that the p38 kinase is not correctly temporary can be active or expressed that the p38 kinase in an inappropriate May be expressed or active that the p38 kinase constitutive or that p38 kinase expression be irregular can. equally may be the cytokine production mediated by the p38 kinase activity is, at inappropriate times, in inappropriate places or in harmful high levels occur.

Corresponding The present application describes a method for treating a condition or condition characterized by p38 kinase activity or cytokines, by the activity p38 kinase are produced, in a subject, administering a therapeutically effective amount of Compound of formula (I) comprises on the subject. The connection can be as a single or polymorphic crystalline form or forms, one amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers single diastereoisomer or a mixture of diastereoisomers be administered.

The The present application also describes a method of inhibiting cytokine production by p38 kinase activity in one Subjects, e.g. To a person, it is conveyed that administering a therapeutic or cytokine inhibiting amount of a compound of the present invention to the subjects, which has a need for a Inhibition of cytokine production has. The connection can be considered a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single Stereoisomer, a mixture of stereoisomers, a single diastereoisomer or a mixture of diastereoisomers.

These conditions can by providing a therapeutically effective amount of a compound thereof Be treated invention. With "therapeutic effective amount "is a symptom-alleviating or symptom-reducing amount, a Cytokine-reducing amount, a cytokine-inhibiting amount, a kinase-regulating Quantity and / or a kinase-inhibiting Amount of a connection meant. Such quantity can be easily obtained by standard methods be determined, such as by measuring cytokine level or Watching the relief of clinical symptoms. For example The practicing physician may have recognized measurement scores for anti-inflammatory Monitor treatments.

The Compounds of the present invention may be administered to any subject who a need for inhibition or regulation of p38 kinase or a Need for inhibition or regulation of p38-mediated cytokine production has to be administered. In particular, the compounds can be administered to mammals become. Such mammals can for example, horses, cows, Sheep, pigs, mice, Dogs, cats, primates, such as chimpanzees, gorillas, Rhesus monkeys and most preferably humans.

A method for treating or reducing symptoms in a human or animal subject, including, for example, rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, chronic heart failure, Silicosis, endotoxemia, toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, aneurysm, stroke, irritable bowel, muscle degeneration, bone wasting, osteoporosis, diabetes , Reperfusion injury, graft-versus-host reaction, allograft rejection, sepsis, systemic cachexia, cachexia in addition to infection or a malignant tumor, cachexia in addition to acquired immunodeficiency syndrome (AIDS), malaria, leprosy, inf ectopic arthritis, leishmaniasis, Lyme disease, glomerulonephritis, gout, psoriatic arthritis, Reiter's syndrome, traumatic arthritis, rubellar arthritis, Crohn's disease, ulcerative colitis, acute synovitis, gouty arthritis, spondylitis and non-articular inflammatory conditions, for example disc prolapse / prolapse / Hernia, bursitis, tendonitis, tenosinovitis, fibromyalgic syndrome and other inflammatory conditions associated with ligament compression and reginal musculoskeletal compressions, pain, for example, associated with inflammation and / or trauma, osteopetrosis, restenosis, thrombosis, angiogenesis, cancer, including breast cancer, colon cancer, lung cancer or prostate cancer, are described as administering a therapeutically effective Amount of a compound of formula (I) comprises on the subject.

method for the treatment of a human or animal subject, the rheumatoid arthritis, asthma, psoriasis, chronic pneumonia, chronic obstructive Lung disease, chronic heart failure, systemic cachexia, Glomerulonephritis, Crohn's disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Including epilepsy and cancer Breast cancer, colon cancer, lung cancer and prostate cancer, are described administering a therapeutically effective Amount of a compound of formula (I) comprises on the subject.

One Method for treating a human or animal subject rheumatoid arthritis, asthma, psoriasis, chronic Lung infection, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease and cancer, including Breast cancer, colon cancer, lung cancer and prostate cancer, is suffering described administering a therapeutically effective Amount of a compound of formula (I) comprises on the subject.

One Method for treating a human or animal subject rheumatoid arthritis, asthma, chronic pneumonia, chronic obstructive Lung disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease and epilepsy suffers is described administering a therapeutically effective amount of a compound of the formula (I) on the subject.

One Method for treating a human or animal subject suffering from any kind of pain, including chronic pain, rapid onset of analgesia, neuromuscular pain, headache, cancer pain, acute and chronic inflammatory pain, associated with osteoarthritis and rheumatoid arthritis, postoperative inflammatory pain, neuropathic pain, diabetic neuropathy, trigeminal Neuralgia, posthepatic neuralgia, inflammatory neuropathy and migraine pain It is described that administering a therapeutic effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvates thereof to the subject.

The Compounds of formula (I) can alone or in combination with other therapeutics for treatment one of the above conditions be used. Especially in rheumatoid arthritis therapy is a combination with other chemotherapeutic or antibody agents imaginable. Combination therapies according to the present invention therefore comprise administering at least one compound of the Formula (I) and at least one other therapeutic agent. The compound (s) of the formula (I) and the other pharmaceutical (s) Active substance (s) can / may administered together or separately, and when administered separately, this can be done separately or sequentially in any order. The Amounts of the compound (s) of formula (I) and the other pharmaceutical Drug (s) and the relative timing the administration is selected to the desired to achieve combined therapeutic effect. Examples of others Pharmaceutical agents used in combination with the compounds of the formula (I) for a rheumatoid arthritis therapy can be used, include the following an immunosuppressant, such as Amtolmetinguacil, Mizoribin and rimexolone; Anti-TNF agents, such as etanercept, infliximab, diacerein; tyrosine kinase inhibitors, such as Leflunmomid; Kallikrein antagonists, such as Subreum; Interleukin-11 agonists such as Oprelvekin; Interferon beta 1 agonists; Hyaluronic acid agonists, such as NRD-101 (Aventis); Interleukin-1 receptor antagonists, such as anakinra; CD8 antagonists, such as amiprilose hydrochloride; beta-amyloid precursor protein antagonists, such as Reumacon; Matrix metalloprotease inhibitors, such as for example, cipemastat and other disease-modifying antirheumatic Medicinal products (DMARD), such as methotrexate, sulphasalazine, Cyclosporin A, hydroxychloroquine, auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.

Examples

The following examples are illustrative embodiments of the invention, not the scope of the invention in any way limit. Reagents are commercially available or according to in the Literature described method produced.

LCMS was on a pillar (3.3 cm x 4.6 mm ID, 3 μm ABZ + PLUS), at a flow rate of 3 ml / min, an injection volume of 5 μl, at room temperature and a UV detection range from 215 to 330 nm performed.

2-chloroisonicotinic acid, 3-cyanobenzenesulfonyl chloride, 3,4-difluorobenzenesulfonyl chloride, 2,3-dihydro-1-benzofuran-5-sulfonyl chloride and 5-isoxazol-3-yl-thiophene-2-sulfonyl chloride may be obtained from Maybridge Chemicals be acquired.

3-iodo-4-methylaniline, 3-fluorobenzenesulfonyl chloride and 4- (trifluoromethyl) benzenesulfonyl chloride can be purchased from avocado.

3-methoxyphenylsulfonyl can be purchased from Lancaster.

4-Acetyphenylsulfonylchlorid can be purchased from Acros.

5-bromoindazole can be prepared by the method described in Chem. Ber. 1922, 55,1141 described is to be produced.

6-Bromo-3-piperidin-4-yl-1,2-benzisoxazole can be prepared by the method described in WO 97/49698 described.

6-bromo-3-methyl-1,2-benzisoxazole and 5-bromo-3-methyl-1,2-benzisoxazole can be prepared according to the procedures described in Indian J. Chem. Sect. B, 1977, 15B, 1058-1063 become.

Methyl 4 - [(chlorosulfonyl) methyl] benzoate can be prepared by the method described in Rec. Trav. Chim. Pays-Bas, 1957, 76, 129. Intermediate 1: 6-bromo-3-bromomethyl-1,2-benzisoxazole

A mixture of 6-bromo-3-methyl-1,2-benzisoxazole (675 mg), N-bromosuccinimide (642 mg) and 1,1'-azobis (cyclohexanecarbonitrile) (90 mg) in carbon tetrachloride (7 ml) was added Using a 300 W lamp at reflux under nitrogen irradiated for 40 h. After cooling, the precipitate was removed by filtration, the solvent was evaporated, and the residue was purified by flash chromatography on a column of silica (4 cm diameter) eluted with a cyclohexane-ethyl acetate gradient (49: 1 to 24: 1). to give the title compound as a pale yellow solid (350 mg).
LC-MS: Rt 3.67 min. Intermediate 2: 2 - [(6-Bromo-1,2-benzisoxazol-3-yl) methyl] amino-1,3-propanediol

A solution of 6-bromo-3-bromomethyl-1,2-benzisoxazole (Intermediate 1, 130 mg), serinol (50 mg) and DIPEA (0.05 ml) in DMF (0.2 ml) were added at 60 ° C stirred under nitrogen for 3 h. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried through a hydrophobic filter and concentrated. The residue was purified on a Varian Bond Elut SPE cartridge (silica, 2 g) eluting with dichloromethane followed by dichloromethane-methanol (9: 1) to give the title compound as a yellow gum (33 mg).
LC-MS: Rt 1.75 min, MH + 301, 303. Intermediate 3: tert -butyl-5-bromo-1H-indazole-1-carboxylate

A stirred ice cold suspension of 5-bromoindazole (2 g, 10.2 mmol), 4- (dimethylamino) pyridine (250 mg, 2.0 mmol) and triethylamine (1.55 mL, 11.2 mmol) in acetonitrile (50 ml) were treated with a solution of di-tert-butyl dicarbonate (2.8 mL, 12.2 mmol) in acetonitrile (20 mL) over a period of 15 minutes so that the temperature remained below 5 ° C. The reaction mixture was warmed to room temperature and then stirred for 18 h. The solvent was evaporated and the residue purified by column chromatography on silica (100 g) eluted with cyclohexane: ethyl acetate (15: 1) to give the title compound (2.27 g, 7.7 mmol).
NMR: δ H [CDCl ₃ ] 8.10 (1H, s), 8.07 (1H, d), 7.86 (1H, d), 7.60 (1H, dd), 1.71 (9H, s ).
LC-MS: Rt 3,55 min. Intermediate 4: 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid

3-iodo-4-methylbenzoic acid (10 g, 38.16 mmol), bis (pinnacolato) dibor (14.5 g, 57.24 mmol), potassium acetate (18.73 g, 190.8 mmol) and PdCl ₂ dpf (3.12 g, 3.8 mmol) in DMF (200 mL) were heated at 80 ° C for 21 h. The solvent was evaporated from the cooled reaction under vacuum, the residue dissolved in ethyl acetate (300 ml) and hydrochloric acid (2N, 300 ml) and filtered through Celite. The organic phase was separated and the aqueous extracted with ethyl acetate (2 x 300 ml). The combined organic extracts were washed with brine (500 ml) and dried (magnesium sulfate). The solvent was evaporated in vacuo and the residue was absorbed on silica and applied to a column of silica. This was eluted with cyclohexane / ethyl acetate (5: 1) to give the title compound.
NMR: δ H [d6-DMSO] 12.83 (1H, b), 8.23 (1H, d), 7.89 (1H, dd), 7.29 (1H, d), 2.51 (3H, s), 1.30 (12H, s).
LC-MS: Rt 3.65 min. Intermediate 5: N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide

Intermediate 4 (10 g) was dissolved in DMF (100 ml). Cyclopropylamine (2.2g), DIPEA (15ml) and HATU (14g) were added thereto. The mixture was stirred for 3 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (400 ml) and saturated sodium bicarbonate solution (400 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to give a pink solid. The product was purified using Biotage chromatography on silica eluted with 50:50 ethyl acetate / cyclohexane to give the title compound as a white solid.
NMR: δH [d6-DMSO] 8.42 (1H, d), 8.06 (1H, d), 7.77 (1H, dd), 7.23 (1H, d), 2.85 (1H, m), 2.47 (3H, s), 1.32 (12H, s), 0.67 (2H, m), 0.56 (2H, m).
LC-MS: Rt 3.29 min, MH ⁺ 302. Intermediate 6: 3-iodo-4-methylbenzoyl chloride

Thionyl chloride (8.2 ml) was added to a mixture of 3-iodo-4-methylbenzoic acid (18.5 g) in chloroform (100 ml) and heated at 61 ° C for 16 hours. The solvent was removed in vacuo and excess thionyl chloride removed by azeotroping with toluene (3 x 30 mL). The title compound was formed as a beige solid (19.5 g) and used in subsequent reactions without further purification.
NMR: δH [d6-DMSO] 8.31 (1H, d), 7.87 (1H, dd), 7.46 (1H, d), 2.43 (3H, s). Intermediate 7: 4- (3-Nitrophenyl) morpholine

3-fluoronitrobenzene (10 g) was added to a solution of morpholine (34 ml) in DMSO (120 ml) and heated at 110 ° C for 60 h. The reaction mixture was cooled and poured into water (800 ml). The precipitate was collected by filtration and the orange solid dried under vacuum and used in the subsequent reaction without further purification (13.7 g).
NMR: δH [d6-DMSO] 7.68 (1H, dd), 7.62 (1H, dd), 7.49 (1H, t), 7.42 (1H, dd), 3.76 (4H, dd), 3.24 (4H, dd). Intermediate 8: 3- (4-morpholinyl) benzenamine

An Erlenmeier flask containing 5% palladium on charcoal (1.95 g) was drained and topped up with hydrogen. 4- (3-Nitrophenyl) morpholine (Intermediate 7) (19.5 g) was added to the Erlenmeier flask as a solution in ethanol and DMF (1000 mL, 4: 1 v / v). The reaction was stirred at room temperature until the further uptake of hydrogen subsides (after about 7 l). The reaction was then filtered through Celite and the solvent removed in vacuo to give the title compound (12.6g) as a beige solid.
NMR: δH [d6-DMSO] 6.85 (1H, t), 6.12 (2H, m), 6.06 (1H, dd), 4.88 (2H, brs), 3.70 (4H, apparent t), 2.98 (4H, apparent t).
LC-MS: Rt 1.08 min MH ⁺ 179. Intermediate 9: 3-iodo-4-methyl-N- [3- (4-morpholinyl) phenyl] benzamide

3-iodo-4-methylbenzoyl chloride (Intermediate (6) (19.5 g) was added portionwise to a mixture of triethylamine (48 ml) and 3- (4-morpholinyl) benzeneamine (Intermediate 8) (12.6 g) in DMF (150 ml) and the mixture was heated at 80 ° C for 16 hours The solvent was removed in vacuo and the residue was dissolved in chloroform (200 ml) The organic layer was washed with water (2 x 100 ml), 2M Sodium hydroxide solution (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo The resulting yellow solid was triturated with diethyl ether and collected by filtration to give the title compound as an off-white solid (20.0 g The product was used in the subsequent reaction without further purification.
NMR: δ H [d6-DMSO] 10.10 (1H, s), 8.39 (1H, d), 7.90 (1H, dd), 7.49 (1H, d), 7.38 (1H, t), 7.28 (1H, brd), 7.19 (1H, t), 6.71 (1H, dd), 3.75 (4H, apparent t), 3.10 (4H, apparent t), 2.44 (3H s).
LC-MS: Rt 3.25 min, MH ⁺ 423. Intermediate 10: 4-methyl-N- [3- (4-morpholinyl) phenyl] -3- (4,4,5,5-tetramethyl- [1, 2,3] -dioxaborolane-2-yl) benzamide

3-iodo-4-methyl-N- [3- (4-morpholinyl) phenyl] benzamide (interm. 9) (8.00g), triethylamine (7.9ml) and bis (pinacolato) diborane (4.13ml ) were added to a solution of PdCl ₂ dppf (770 mg) in dioxane (100 ml) and the mixture was heated at 80 ° C under nitrogen for 3 h. The reaction was cooled, the solvent removed in vacuo and the residue dissolved in dichloromethane (150 ml). The solution was washed with water (3 × 100 ml) and brine (100 ml), dried (magnesium sulfate), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica eluted with 30% ethyl acetate / cyclohexane to 50% ethyl acetate / cyclohexane to give the title compound as a white solid (4.05 g).
NMR: δ H [d6-DMSO] 10.11 (1H, s), 8.19 (1H, d), 7.93 (1H, dd), 7.40 (1H, brs), 7.33 (1H, d), 7.28 (1H, brd), 7.19 (1H, t), 6.70 (1H, dd), 3.75 (4H, apparent t), 3.09 (4H, apparent t), 2.54 (3H, s), 1.33 (12H, s).
LC-MS: Rt 3.65 min, MH ⁺ 423. Intermediate 11: 2-chloro-N- (3-iodo-4-methylphenyl) -isonicotinamide

2-chloroisonicotinic acid (3.3g), HATU (8.75g), DIPEA (10.9ml) and 3-iodo-4-methylaniline (5.00g) in DMF (50ml) were added under nitrogen for 16 h heated. The reaction was cooled, the solvent removed in vacuo and the residue dissolved in dichloromethane (150 ml). The solution was washed with water (3 x 100 mL) and brine (100 L), dried (magnesium sulfate), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica eluted with ethyl acetate / cyclohexane (40: 6) to give the title compound as a white solid (7.00 g).
NMR: δH [d6-DMSO] 10.52 (1H s), 8.62 (1H, d), 8.29 (1H, d), 7.99 (1H, b), 7.87 (1H, dd ), 7.70 (1H, dd), 7.34 (1H, d), 2.36 (3H, s).
LC-MS: Rt 3.59 min, MH ⁺ 373. Intermediate 12: N- (3-iodo-4-methylphenyl) -2-pyrrolidin-1-yl isonicotinamide

A solution of N- (3-iodo-4-methylphenyl) -2-chloro-isonicotinamide (interm. 11) (7.00g) in pyrrolidine (20ml) was heated at 80 ° C under nitrogen for 16h. Excess pyrrolidine was removed in vacuo and the residue was triturated with diethyl ether (20 ml). The resulting solid was collected by filtration and dried under vacuum to give the title compound as a pale yellow solid (7.73 g).
NMR: δH [d6-DMSO] 10.29 (1H, s), 8.29 (1H, d), 8.20 (1H, d), 7.71 (1H, dd), 7.72 (1H, dd), 6.97 (1H, brd), 6.88 (1H, b), 3.45 (2H, apparent t), 3.09 (2H, m), 2.35 (3H, s), 1 , 98 (2H, m), 1.82 (2H, m).
LC-MS: Rt 2.77 min, MH ⁺ 408. Intermediate 13: N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl ) phenyl] -2- (1-pyrrolidinyl) -4-pyridinecarboxamide

Bis (pinacolato) diborane (7.24 g) was added to a mixture of N- (3-iodo-4-methylphenyl) -2-pyrrolidin-1-yl isonicotinamide (interm. 12) (7.73 g), potassium acetate ( 9.32g, 95mmol) and PdCl ₂ dppf (770mg) in DMF (100ml) and the reaction was heated at 80 ° C under nitrogen for 16 hours. The reaction was cooled and the solvate was removed in vacuo. The residue was dissolved in chloroform (150 ml), washed with water (3 × 100 ml) and brine (100 ml), dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography on silica eluted with ethyl acetate: cyclohexane (1: 4) to (1: 1) to give the title compound as a white solid (1.5 g).
NMR: δ H [CDCl ₃ ] 8.27 (1H, d), 7.99 (1H, dd), 7.76 (1H, b), 7.65 (1H, d), 6.20 (1H, d ), 6.82 (1H, b), 6.77 (1H, b), 3.52 (4H, apparent t), 2.52 (3H, s), 2.25 (4H, m), 1, 35 (12H, s).
LC-MS: Rt 2.90 min, MH ⁺ 408. Intermediate 14: N- (3-iodo-4-methylphenyl) thiophene-3-amide

Thiophene-3-carboxylic acid (2.75 g) and HATU (8.15 g) in DMF (25 ml) were stirred at room temperature for 15 min. HOBT (2.9 g), 3-iodo-4-methylaniline (5.0 g) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction was stirred at room temperature for 16 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic Phase was dried (magnesium sulfate) and absorbed on silica. The silica was applied to a column of silicic acid and eluted with cyclohexane / ethyl acetate (4: 1). The solvent was evaporated from the product fractions under vacuum to give the title compound.
NMR: δH [d6-DMSO] 10.06 (1H, b), 8.34 (1H, m), 8.29 (1H, d), 7.70 (1H, dd), 7.66 (1H, dd), 7.62 (1H, dd), 7.30 (1H, d), 2.34 (3H, s).
LC-MS: Rt 3.69 min, MH ⁺ 344. Intermediate 15: N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl ) phenyl] thiophene-3-amide

N- (3-iodo-4-methylphenyl) thiophene-3-amide (Intermediate 14) (2.64g), bis (pinnacolato) dibor (2.13g), potassium acetate (825mg) and PdCl ₂ dppf (312 mg) in DMF (20 ml) were heated at 80 ° C for 20 h. The cooled reaction was absorbed onto silica and applied to a Varian Bond Elut SPE cartridge (silica, 10 g) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum to give the title compound.
NMR: δH [d6-DMSO] 9.99 (1H, b), 8.35 (1H, s), 7.90 (1H, d), 7.85 (1H, dd), 7.63 (2H, m), 7.14 (1H, d), 2.42 (3H, s), 1.30 (12H, s).
LC-MS: Rt 3.65 min, MH ⁺ 344. Intermediate 16: N- (3-iodo-4-methylphenyl) -3-furamide

3-Fluoroic acid (2.4 g) and HATU (8.15 g) in DMF (25 ml) were stirred at room temperature for 15 min. HOBT (2.9 g), 3-iodo-4-methylaniline (5.0 g) and DIPEA (11.2 ml) were added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases were washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulfate) and absorbed on silica. The silica was applied to a column of silicic acid and eluted with cyclohexane / ethyl acetate (3: 1) to give the title compound.
NMR: δ H [d6-DMSO] 9.92 (1H, b), 8.36 (1H, d), 8.23 (1H, d), 7.80 (1H, t), 7.66 (1H, dd), 7.29 (1H, d), 6.98 (1H, d), 2.33 (3H, s).
LC-MS: Rt 3.52 min, MH ⁺ 328. Intermediate 17: N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] -3-furamide

N- (3-iodo-4-methylphenyl) -3-furamide (interm. 16) (2.5g), bis (pinnacolato) dibor (2.13g), potassium acetate (825mg) and PdCl ₂ dppf (312mg ) in DMF (20 ml) were heated at 80 ° for 20 h. The cooled reaction was absorbed on silica and applied to a Varian Bond Elut SPE cartridge (silica, 10 g). applied and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under vacuum to give the title compound.
NMR: δH [d6-DMSO] 9.86 (1H, b), 8.36 (1H, m), 7.86-7.82 (2H, m), 7.77 (1H, t), 7, 14 (1H, d), 6.99 (1H, m), 2.41 (3H, s), 1.30 (12H, s).
LC-MS: Rt 3.55 min, MH ⁺ 328. Intermediate 18: 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiazol-2-yl) -benzamide

4-Methyl-3- (4,4,5,5-tetramethyl- [1,2,3] dioxaborolan-2-yl) -benzoic acid (Intermediate 4) (2.0 g), DIPEA (4 ml) and HATU (3.05 g) were dissolved in DMF (20 ml) and stirred at room temperature for 15 min. 2-Aminothiazole (801 g) was added and the mixture was stirred at room temperature for 18 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic phase was washed with hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml), dried (magnesium sulfate) and concentrated in vacuo. The residue was absorbed onto silica and purified by flash column chromatography eluted with cyclohexane / ethyl acetate (4: 1) to give the title compound (1.72 g).
NMR: δH [d6-DMSO] 12.65 (1H, b), 8.32 (1H, d), 8.08 (1H, dd), 7.56 (1H, d), 7.35 (1H, d), 7.28 (1H, d), 2.54 (3H, s), 1.34 (12H, s).
LC-MS: Rt 3.66 min, MH ⁺ 345. Intermediate 19: N- (3-methoxy-phenyl) -4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2 ] dioxaborolan-2-yl) -benzamide

4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid (Intermediate 4 (2 g) was dissolved in DMF (20 ml) 3-methoxyaniline (0.985g), DIPEA (4ml) and HATU (3.05g) were added and the mixture was stirred at room temperature for 18h The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (250ml The organic layer was dried (magnesium sulfate), concentrated under vacuum and purified using a silica biotage cartridge (90 g), eluted with 1: 4 ethyl acetate / cyclohexane, to give the title compound as a to give a white solid (2.06 g).
NMR: δH [d6-DMSO] 10.20 (1H, s), 8.17 (1H, s), 7.94-7.91 (1H, dd), 7.45 (1H, s), 7, 36-7.32 (2H, t), 7.25-7.21 (1H, t), 6.68-6.65 (1H, dd), 3.74 (3H, s), 2.53 ( 3H, s), 1.32 (12H, s).
LC-MS: Rt 3.80 min, MH ⁺ 368. Intermediate 20: 4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl-N - ([1,3,4] thiadiazol-2-yl) - benzamide

4-Methyl-3- (4,4,5,5-tetramethyl- [1,2,3] dioxaborolan-2-yl) -benzoic acid (Intermediate 4) (2.0 g), DIPEA (4 ml) and HATU (3.05 g) were dissolved in DMF (20 ml) and stirred at room temperature for 15 min. 2-Aminothiadiazole (810 mg) was added and the mixture was stirred at room temperature for 18 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (250 ml) and hydrochloric acid (2N, 150 ml). The aqueous phase was extracted with ethyl acetate (2 × 250 ml). The combined organic extracts were dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4: 1 then 1: 1) to give the title compound (0.95 g).
NMR: δH [d6-DMSO] 13.08 (1H, b), 9.22 (1H, s), 8.35 (1H, d), 8.11 (1H, dd), 7.38 (1H, d), 2.55 (3H, s), 1.34 (12H, s).
LC-MS: Rt 3.34 min, MH ⁺ 346. Intermediate 21: N-cyclopropylmethyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl ) -benzamide

4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl] -benzoic acid (Intermediate 4) (2.0 g), DIPEA (4 ml) and HATU (3.05g) was dissolved in DMF (20ml) and stirred at room temperature for 15 min Cyclopropylmethylamine (568mg) was added and the mixture was stirred at room temperature for 18h The solvent was removed in vacuo, and the solvent was removed Residue was partitioned between ethyl acetate (250ml) and water (50ml) The organic phase was washed with hydrochloric acid (2N, 50ml) and aqueous sodium bicarbonate (1M, 50ml), dried (magnesium sulphate) and concentrated in vacuo was absorbed onto silica and purified by "flash" column chromatography eluted with cyclohexane / ethyl acetate (4: 1) to give the title compound (1.73 g).
NMR: δ H [d6-DMSO] 8.54 (1H, t), 8.11 (1H, d), 7.82 (1H, dd), 7.26 (1H, d), 3.12 (2H, t), 1.32 (12H, s), 1.03 (1H, m), 0.42 (2H, m), 0.22 (2H, m).
LC-MS: Rt 3.47 min, MH + 316. Intermediate 22: methyl 4-bromo-2-hydroxybenzoate

A solution of 4-bromo-2-hydroxybenzoic acid (1.0g) in methanol (10ml) was cautiously treated with conc. Sulfuric acid (0.5ml) and then stirred at 75 ° C under nitrogen for 7h. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (30 ml) and water (30 ml). The aqueous layer was back extracted with ethyl acetate (30 mL) and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (2 x 50 mL) and water (50 mL) rule. The dried (MgSO ₄ ) extracts were concentrated under vacuum to give the title compound as a beige solid (0.7 g).
LC-MS: Rt 3.42 min. Intermediate 23: 4-bromo-N, 2-dihydroxybenzamide

A solution of methyl 4-bromo-2-hydroxybenzoate (interm. 22) (0.7g) in dioxane (5ml) was added to a solution of hydroxylamine hydrochloride (0.32g) and sodium hydroxide (0.42g) in water (10 ml) was added dropwise and then stirred at room temperature for 18 h. The dioxane was removed in vacuo and the residue was stirred with 2N hydrochloric acid to give a precipitate, which was collected by filtration, washed with water and dried to give the title compound as an off-white solid (0.63 g).
LC-MS: Rt 2.64 min. Intermediate 24: 6-bromo-1,2-benzisoxazol-3- (3H) -one

A solution of carbonyldiimidazole (0.75g) in dry tetrahydrofuran (15ml) was added to a refluxed solution of 4-bromo-N, 2-dihydroxybenzamide (interm. 23) (0.56g) in dry tetrahydrofuran (10ml) , and then stirred for 2 h. The solvent was removed in vacuo, the residue suspended in water and 2N hydrochloric acid (10 ml) added. The resulting precipitate was collected by filtration, washed with water and then with cyclohexane and dried to give the title compound as an off-white solid (0.37 g).
LC-MS: Rt 3.30 min. Intermediate 25: 1,1-dimethylethyl 4- (6-bromo-1,2-benzisoxazol-3-yl) -1-piperazinecarboxylate

An ice bath-cooled solution of 6-bromo-1,2-benzisoxazol-3 (2H) -one (Intermediate 24) (0.05 g) and dry pyridine (0.05 ml) in dry dichloromethane (4 ml) was added Nitrogen stirred and treated with trifluoromethanesulfonic anhydride (60 μl). The solution was stirred at room temperature for 4 h, diluted with cyclohexane, then applied to a Varian Bond Elut SPE cartridge (silica, 1 g) and eluted with dichloromethane to give a yellow oil. The oil was dissolved in acetonitrile (2 mL), treated with 1,1-dimethylethyl-1-piperazinecarboxylate (0.04 g) and diisopropylethylamine (0.05 mL) and then stirred at 70 ° C under nitrogen for 20 h. The cooled reaction mixture was purified on a Varian Bond Elut SPE cartridge (silica, 5 g) using dichloromethane: methanol to give the title compound as a white solid (0.016 g).
LC-MS: Rt 3.62 min. Intermediate 26: 1,1-dimethylethyl 4- (6- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1,2-benzisoxazol-3-yl) -1-piperazinecarboxylate

A mixture of 1,1-dimethylethyl 4- (6-bromo-1,2-benzisoxazol-3-yl) -1-piperazinecarboxylate (Intermediate 25) (0.04 g), N-cyclopropyl-4-methyl-3 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (interm. 5) (0.035g), 2N aqueous sodium carbonate (2ml) and tetrakis (triphenylphosphine) palladium (0 ) (1 mg) in isopropanol (6 ml) was stirred at reflux under nitrogen for 16 h. The residue was absorbed on silica (Merck 7734) and applied to a Varian Bond flood SPE cartridge (silica, 5 g). Elution with dichloromethane: methanol (98: 2) gave the title compound as an off-white solid (0.03 g).
LC-MS: Rt 3.50 min. Intermediate 27: 6-bromo-4- (4-morpholinyl) -1,2-benzisoxazole

An ice-bath cooled solution of 6-bromo-1,2-benzisoxazol-3 (2H) -one (Intermediate 24) (0.15g) and dry pyridine (0.15ml) in dry dichloromethane (12ml) was added Nitrogen stirred and treated with trifluoromethanesulfonic anhydride (180 μl). The solution was stirred at room temperature for 90 minutes, diluted with cyclohexane, then applied to a Varian Bond flood SPE cartridge (silica, 5 g) and eluted with cyclohexane and dichloromethane to give a colorless oil. The oil was dissolved in acetonitrile (4 ml), treated with morpholine (61 μl) and diisopropylethylamine (0.15 ml) and then stirred at 70 ° C under nitrogen for 16 h. The cooled reaction mixture was purified via a Varian Bond flood SPE cartridge (silica, 5 g) using dichloromethane: ethanol: 0.88 ammonia to give the title compound as a white solid (0.03 g).
LC-MS: Rt 3.01 min. Intermediate 28: 3-bromophenylacetate

Acetic anhydride was added dropwise to an ice cold solution of 3-bromophenol (55 g) in pyridine (25 ml) and the solution was then stirred at room temperature for 4 h. 2N hydrochloric acid (160 ml) was added and the mixture was extracted with ether (2 times). The combined organic extracts were washed with water and brine, dried (magnesium sulfate) and concentrated under vacuum to give the title compound as a brown liquid (30.8 g).
LC-MS: Rt 3.0 min. Intermediate 29: 1- (4-bromo-2-hydroxyphenyl) ethanol

3-Bromophenylacetate (Intermediate 28) (30.6 g) was added portionwise to powdered aluminum chloride (15.5 g) with stirring. The resulting liquid was stirred at 170 ° C under nitrogen for 1 hour and then at 70 ° C for 2 hours. 2N hydrochloric acid (150 ml) was added and the mixture was allowed to cool to room temperature. The mixture was extracted with ethyl acetate (2 times) and the solvent was evaporated to leave a dark oil which was purified on silica (500 g) eluted with cyclohexane: ethyl acetate (4: 1) to give the title compound as to give a light colored semi-solid (26.8 g).
LC-MS: Rt 3.2 min. Intermediate 30: Ethyl 3- (4-bromo-2-hydroxyphenyl) -3-oxo-propanoate

A solution of ethyl 3- (4-bromo-2-hydroxyphenyl) -3-oxopropanoate (interm. 29) (30 g) in dry toluene (10 ml) was added to a stirred suspension of sodium hydride (60% oil dispersion, 1, 54 g) in dry toluene (15 ml) was added dropwise at reflux under nitrogen. After the addition, stirring was continued for a further 10 minutes and diethyl carbonate (3.39 ml) was added over a period of 30 minutes. The mixture was then stirred at reflux for 18 h. After cooling, ice-cold 2N hydrochloric acid (150 ml) was added and the mixture was extracted with ethyl acetate (2 x 100 ml). The combined extracts were washed with water and brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica (100 g), eluted with cyclohexane: ethyl acetate (10: 1), to give the title compound as an off-white solid (2.87 g).
LC-MS: Rt 3.25 min. Intermediate 31: 7-Bromo-4-hydroxy-2H-chromen-2-one

A solution of ethyl 3- (4-bromo-2-hydroxyphenyl) -3-oxopropanoate (interm. 30) (2.0 g) in dry toluene (20 ml) was stirred at reflux under nitrogen for 24 h. After cooling, the resulting precipitate was collected by filtration, washed with ether and dried to give the title compound as a white solid (1.32 g).
LC-MS: Rt 3.47 min. Intermediate 32: (6-bromo-1,2-benzisoxazol-3-yl) acetic acid

Sodium metal (0.36 g) was dissolved in dry ethanol (30 ml) and then treated with hydroxylamine hydrochloride (1.12 g). A solution of 7-bromo-4-hydroxy-2H-chromen-2-one (interm. 31) (1.3g) in dry ethanol (30ml) was added and the mixture was refluxed under nitrogen for 3.5h touched. After cooling, the mixture was added to 2M aqueous sodium bicarbonate (100 ml). Water (100 ml) and dichloromethane (100 ml) were added, the phases were separated and the aqueous layer was washed with more dichloromethane (75 ml). The aqueous layer was acidified by the careful addition of 2N hydrochloric acid to afford a precipitate, which was collected by filtration and dried to give the title compound as a white solid (1.06 g).
LC-MS: Rt 2.99 min. Intermediate 33: 1,1-dimethylethyl 4 - [(6-bromo-1,2-benzisoxazol-3-yl) acetyl] -1-piperazinecarboxylate

A suspension of (6-bromo-1,2-benzisoxazol-3-yl) acetic acid (interm. 32) (0.06g) and HATU (0.09g) in dry tetrahydrofuran (2ml) was added at room temperature for 5 min touched. 1-Hydroxybenzotriazole (0.03 g) and 1,1-dimethylethyl-1-piperazinecarboxylate (0.04 g) were added and the reaction mixture was stirred for a further 18 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and 2N aqueous sodium carbonate. The layers were separated and the organic layer was applied to a Varian Bond flood SPE cartridge (silica, 5 g), sequentially eluted with dichloromethane, chloroform, ether and ethyl acetate to give the title compound as a white solid (0.09 g).
LC-MS: Rt 3.21 min. Intermediate 34: 1,1-dimethylethyl 4 - [(6- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1,2-benzisoxazol-3-yl) acetyl] -1-piperazinecarboxylate

A mixture of 1,1-dimethylethyl 4 - [(6-bromo-1,2-benzisoxazol-3-yl) acetyl] -1-piperazinecarboxylate (interm. 33) (0.045 g) N-cyclopropyl-4-methyl-3 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (interm. 5) (0.03 g) and 2M aqueous sodium carbonate (0.65 ml) in isopropanol (2, 5 ml) under nitrogen was treated with tetrakis (triphenylphosphine) palladium (0) (1 mg) and then stirred at reflux for 18 h. After cooling, the mixture was absorbed onto silica (Merck 7734) and applied to a Varian Bond Flood SPE cartridge (silica, 5 g). Sequential elution with dichloromethane, chloroform, ether, ethyl acetate, acetonitrile and acetone afforded the title compound as a white solid (0.03 g).
LC-MS: Rt 3.16 min. Intermediate 35: 2- (6-Bromo-1,2-benzisoxazol-3-yl) -N- (2-hydroxyethyl) acetamide

A suspension of (6-bromo-1,2-benzisoxazol-3-yl) acetic acid (interm. 32) (0.10g) and HATU (0.18g) in tetrahydrofuran (5ml) was stirred at room temperature for 10 minutes and then treated with 1-hydroxybenzotriazole (0.05 g), 2-aminoethanol (0.03 ml) and diisopropylethylamine (0.2 ml). The mixture was stirred for an additional 18 h and then concentrated under vacuum. The residue was partitioned between dichloromethane (5ml) and 2M aqueous sodium carbonate (5ml). The organic layer was dried using a hydrophobic filter bag and then applied to a Varian Bond Flood SPE cartridge. Sequential elution with dichloromethane, ether, ethyl acetate, acetonitrile and acetone afforded the title compound as a white solid (0.08 g).
LC-MS: Rt 2.42 min. Intermediate 36: 6-bromo-3- [2-oxo-2- (1-piperidinyl) ethyl] -1,2-benzioxazole

The procedure for Intermediate 35 was followed using piperidine (0.05 ml) instead of 2-aminoethanol to give the title compound as a white solid (0.10 g).
LC-MS: Rt 3.09 min. Intermediate 37: 2- (6-bromo-1,2-benzisoxazol-3-yl) -N-methylacetamide

The procedure for Intermediate 35 was followed using a solution of methylamine in tetrahydrofuran (2M, 0.235 mL) instead of 2-aminoethanol to give the title compound as a white solid (0.10 g).
LC-MS: Rt 2.59 min. Intermediate 38: 2- (6-bromo-1,2-benzisoxazol-3-yl) -N- (3-hydroxypropyl) acetamide

The procedure for Intermediate 35 was followed using 3-aminopropanol (0.04 ml) instead of 2-aminoethanol to give the title compound as a white solid (0.09 g).
LC-MS: Rt 2.48 min. Intermediate 39: 2- (6-bromo-1,2-benzisoxazol-3-yl) -N- (cyclopropylmethyl) acetamide

The procedure for Intermediate 35 was followed using cyclopropylmethylamine (0.04 ml) instead of 2-aminoethanol to give the title compound as a white solid (0.11 g).
LC-MS: Rt 2.99 min. Intermediate 40: 6-bromo-3- [2-oxo-2- (1-pyrrolidinyl) ethyl] -1,2-benzisoxazole

The procedure for Intermediate 35 was followed using pyrrolidine (0.04 ml) instead of 2-aminoethanol to give the title compound as a white solid (0.10 g).
LC-MS: Rt 2.87 min. Intermediate 41: 2- (6-bromo-1,2-benzisoxazol-3-yl) -N-ethylacetamide

The procedure for Intermediate 35 was followed using ethylamine in tetrahydrofuran (0.235 ml) instead of 2-aminoethanol to give the title compound as a white solid (0.09 g).
LC-MS: Rt 2.74 min. Intermediate 42: 2- (6-bromo-1,2-benzisoxazol-3-yl) -N-cyclopropylacetamide

The procedure for Intermediate 35 was followed using cyclopropylamine (0.03 ml) instead of 2-aminoethanol to give the title compound as a white solid (0.08 g).
LC-MS: Rt 2.78 min. Intermediate 43: 6-bromo-3- [2- (4-morpholinyl) -2-oxoethyl] -1,2-benzisoxazole

The procedure for Intermediate 35 was followed using morpholine (0.04 ml) instead of 2-aminoethanol to give the title compound as a white solid (0.10 g).
LC-MS: Rt 2.69 min. Intermediate 44: 2- (6-Bromo-1,2-benzisoxazol-3-yl) - N - {[3- (methyloxy) phenyl] methyl} acetamide

The procedure for Intermediate 35 was followed using 3-methoxybenzylamine (0.06 ml) instead of 2-aminoethanol to give the title compound as a white solid (0.10 g).
LC-MS: Rt 3.20 min. Intermediate 45: 2- (6-Bromo-1,2-benzisoxazol-3-yl) -N-1,3-thiazol-2-ylacetamide

The procedure for Intermediate 35 was followed using 2-amino-1,3-thiazole (0.05 ml) instead of 2-aminoethanol to give the title compound as a white solid (0.06 g).
LC-MS: Rt 3.11 min. Intermediate 46: 6-bromo-3 - [(4-methyl-1-piperazinyl) methyl] -1,2-benzisoxazole

A solution of Intermediate 1 (0.06g), 1-methylpiperazine (0.05ml) and diisopropylethylamine (0.1ml) in DMF (0.5ml) was stirred at 65 ° C for 4h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate and the aqueous layer back-extracted with ethyl acetate. The organic extracts were washed with water (2x) and brine, dried using a hydrophobic filter bag and concentrated under a stream of nitrogen. The residue was purified via a Varian Bond flood SPE cartridge (silica, 2 g), eluted with dichloromethane: methanol: ethylamine (100: 0: 1 to 95: 5: 1), to afford the title compound as a pale yellow solid ( 0.04 g).
LC-MS: Rt 2.07 min. Intermediate 47: 6-bromo-3- (1-piperidinylmethyl) -1,2-benzisoxazole

The procedure for Intermediate 46 was followed using piperidine (0.05 ml) instead of 1-methylpiperazole. Elution of the SPE cartridge with cyclohexane: ethyl acetate: triethylamine (100: 0: 1 to 80: 20: 1) gave the title compound as a pale yellow solid (0.03 g).
LC-MS: Rt 2.00 min. Intermediate 48: 6-bromo-3- (4-morpholinylmethyl) -1,2-benzisoxazole

The procedure for Intermediate 46 was followed using morpholine (0.05 ml) instead of 1-methylpiperazine. Elution of the SPE cartridge with cyclohexane: ethyl acetate: triethylamine (100: 0: 1 to 66: 33: 1) gave the title compound as a pale yellow solid (0.04 g).
LC-MS: Rt 2.46 min. Intermediate 49: 6-bromo-3- (1-pyrrolidinylmethyl) -1,2-benzisoxazole

The procedure for Intermediate 46 was followed using pyrrolidine (0.05 ml) instead of 1-methylpiperazine. Elution of the SPE cartridge with cyclohexane: ethyl acetate: triethylamine (100: 0: 1 to 80: 20: 1) gave the title compound as a pale yellow solid (0.03 g).
LC-MS: Rt 1.88 min. Intermediate 50: 4-bromo-2-fluorobenzaldehyde oxime

A solution of hydroxylamine in water (50%, 5 ml) was added to a solution of 4-bromo-2-fluorobenzaldehyde (1, g) in ethanol (5 ml) and the mixture was stirred at room temperature for 66 h. The ethanol was removed in vacuo and the aqueous residue extracted with ethyl acetate (2x). The organic extracts were washed with water and brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified on a Varian Bond flood SPE cartridge (silica, 20 g) eluted with cyclohexane: ethyl acetate (100: 0 to 50:50) to give the title compound as a white solid (0.94 g). to surrender.
LC-MS: Rt 3.15 min. Intermediate 51: 4-Bromo-2-fluoro-N-hydroxybenzenecarboximidoyl chloride

N-chlorosuccinimide (0.075g) was added to a solution of 4-bromo-2-fluorobenzaldehyde oxime (intermediate 50) (0.44g) in DMF (1ml) and then heated at 55 ° C for several minutes. The mixture was allowed to cool to <50 ° C and then more N-chlorosuccinimide (0.22 g) was added. After a few minutes, the mixture was allowed to cool to room temperature and was then partitioned between water and ether. The layers were separated, the aqueous layer back extracted with ether (2x), and the combined organic extracts were washed with water and brine, dried (MgSO ₄ ) and concentrated in vacuo to give a white solid (0.46 g) ,
LC-MS: Rt 3.11 min. Intermediate 52: 4-bromo-N-cyclopropyl-2-fluoro-N'-hydroxybenzenecarboximidamide

Cyclopropylamine (1.6 ml) was added dropwise to an ice-cold solution of 4-bromo-2-fluoro-N-hydroxybenzenecarboximidoyl chloride (interm. 51) (0.59 g) in dry ether (25 ml) under nitrogen. After the addition, the mixture was allowed to warm to room temperature, and was then stirred for 18 hours. The resulting precipitate was collected by filtration, then purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (3: 2) to give the title compound as a white solid (0.435 g).
LC-MS: Rt 2.69 min. Intermediate 53: 6-bromo-N-cyclopropyl-1,2-benzisoxazol-3-amine

1,8-Diazabicyclo [5.4.0] undec-7-ene (0.12 ml) was added to 4-bromo-N-cyclopropyl-2-fluoro-N'-hydroxybenzenecarboximidamide (interm. 52) (0.2 g) Tetrahydrofuran (2 ml) was added and then heated in a microwave at 150 ° C for 70 min. The mixture was applied to a Varian Bond Elut SPE cartridge (silica, 20 g), then eluted with cyclohexane: ethyl acetate (100: 0 to 80:20) to give the title compound as a white solid (0.13 g). to surrender.
LC-MS: Rt 3.16 min. Intermediate 54: methyl (4-bromo-2-nitrophenyl) acetate

Concentrated hydrochloric acid (1 ml) was added to a solution of (4-bromo-2-nitrophenyl) acetic acid (7.07 g) and the solution was stirred at reflux for 5 h. The solvent was evaporated to leave the title compound as a crystalline brown solid (7.39 g).
LC-MS: Rt 3.13 min. Intermediate 55: ethyl 6-bromo-1,2-benzisoxazole-3-carboxylate

Sodium metal (0.09 g) was dissolved in absolute ethanol (2 ml) under nitrogen. A solution of (4-bromo-2-nitrophenyl) acetate (Intermediate 54) (1.0 g) in ethanol (8 mL) was treated with isoamyl nitrite (0.6 mL) followed by the sodium ethoxide solution, giving a black Mixture brought forth. The mixture was stirred at 60 ° C for 90 minutes, then left at room temperature for 18 hours. 2N hydrochloric acid (20 ml) was added and the mixture was extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were washed with water (2x) and brine, dried using a hydrophobic filter bag and concentrated under vacuum. The residue was purified via a Varian Bond flood SPE cartridge eluted with cyclohexane: ethyl acetate (100: 0 to 97: 3) to give the title compound as an off-white solid (577 mg).
LC-MS: Rt 3.40 min. Intermediate 56: 6-bromo-N- (cyclopropylmethyl) -1,2-benzisoxazole-3-carboxamide

A solution of ethyl 6-bromo-1,2-benzisoxazole-3-carboxylate (interm. 55) (0.05g) and cyclopropylamine (0.03ml) in methanol (1ml) was stirred at reflux for 6h. The solvent was evaporated and the residue was triturated with ether to give the title compound as a white solid (0.04 g). Intermediate 57: 6-bromo-N-propyl-1,2-benzisoxazole-3-carboxamide

The procedure of Intermediate 56 was followed using propylamine (0.025 ml) instead of cyclopropylmethylamine to give the title compound as a white solid (0.04 g).
LC-MS: Rt 3.30 min. Intermediate 58: 6-bromo-N-methyl-1,2-benzisoxazole-3-carboxamide

The procedure for Intermediate 56 was followed using a solution of methylamine in methanol (2M, 0.45 mL) instead of cyclopropylmethylamine to give the title compound as a white solid (0.03 g).
LC-MS: Rt 2.92 min Intermediate 59: 6-bromo-N, N-dimethyl-1,2-benzisoxazole-3-carboxamide

The procedure for Intermediate 56 was followed using a solution of dimethylamine in methanol (2M, 0.13 ml) instead of cyclopropylmethylamine to give the title compound as a white solid (0.02 g).
LC-MS: Rt 2.88 min. Intermediate 60: 6-bromo-N-cyclopropyl-1,2-benzisoxazole-3-carboxamide

The procedure for Intermediate 56 was followed using cyclopropylamine (0.025 ml) instead of cyclopropylmethylamine to give the title compound as a white solid (0.05 g).
LC-MS: Rt 3.30 min. Intermediate 61: 3-bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide

3-Fluoro-4-methylbenzoic acid (0.46 g) was added to a stirred mixture of bromine (2.31 ml) and iron powder (0.25 g) under nitrogen. The reaction was stirred at 20 ° C for 4 h and then for 16 h let stand. A sodium thiosulfate solution (200 ml) was added and the product was extracted into ethyl acetate (3 x 150 ml). The ethyl acetate extracts were combined and concentrated under vacuum. The crude product was dissolved in DMF (7 mL) and cyclopropylamine (0.28 mL), 1-hydroxybenzotriazole (0.405 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.575 g) and diisopropylethylamine (0.52 mL). were added. The mixture was stirred for 5 h at 20 ° C. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The combined organic extracts were washed with aqueous sodium bicarbonate and hydrochloric acid (0.5M), dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (6: 1) to give the title compound (359 mg).
LC-MS: MH ⁺ 272. Intermediate 62: N-cyclopropyl-3-fluoro-4-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide

3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (interm. 61) (900mg), bispinnacolato diboron (4.5g), potassium acetate (2.1g) and PdCl ₂ dppf (75mg) were dissolved in DMF (40 ml) and heated at 100 ° C for 18 h. The cooled reaction was absorbed onto silica and applied to a Varian Bond flood SPE cartridge (silica, 2 x 10g) and eluted with cyclohexane: ethyl acetate (100: 0 to 94: 6) The solvent was removed in vacuo, and the residue was recrystallized from cyclohexane to give the title compound (260 mg).
LC-MS: Rt 3.39 min. Intermediate 63: N-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide

N-iodosuccinimide (22.5 g) was added in one part to a solution of 3-fluoro-4-methylbenzoic acid (15.4 g) in trifluoromethanesulfonic acid (100 ml) at 0 ° C over 3 h, and the mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into ice / water (400 ml) and the precipitate was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulfate (2x) and brine, dried (MgSO ₄ ), and the solvent removed in vacuo. The residue was treated with thionyl chloride (30 ml) and heated at 100 ° C for 2.5 h. Excess thionyl chloride was removed in vacuo and the residue was dissolved in dichloromethane (100 ml). Sodium carbonate (25 g) and cyclopropylamine (13 ml) were added to the solution, and the mixture was stirred at room temperature for 72 hours. The mixture was filtered and the residue was washed with dichloromethane and ethyl acetate. The combined filtrates and washes were concentrated under vacuum. The residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (78:22 to 72:28) to give the title compound.
LC-MS: Rt 3.16 min. Intermediate 64: {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} boric acid

N-cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (interm. 63) (5g) in tetrahydrofuran (75ml) was cooled to 0 ° C, then sodium hydride (60% oil dispersion, 1.23g ) was treated in portions over 10 minutes. After the foaming had ceased, the reaction was cooled to -75 ° C and n-butyllithium (1.6 M in hexane, 20 mL) was added over a period of 20 min maintaining a temperature of <-70 ° C , Triisopropyl borate (8 ml) was added over a period of 10 minutes and the mixture was stirred at -70 ° C for 4 h. Water (20 ml) was added and the mixture was allowed to warm to 5 ° C. The solvent was removed in vacuo and the residue was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in dichloromethane / ethyl acetate and purified by column chromatography on silica eluted with dichloromethane: ethyl acetate (95: 5 to 0: 100), then methanol, to give the title compound.
LC-MS: Rt 2.19 min. Intermediate 65: 1-acetyl-6-bromo-1H-indazole

A solution of 4-bromo-2-methylaniline (10.0 g) in chloroform (100 ml) was treated with acetic anhydride (11.5 g) and potassium acetate (5.8 g), then stirred at 55 ° C for 5 h to give a thick suspension. t-Butyl nitrite (19.2 ml) and 18-crown-6 (28.4 g) were added to give a solution which was stirred at 55 ° C for a further 21 h. The solvent was evaporated and the oily residue was eluted through a pad of silica (150 g) using cyclohexane: ethyl acetate (4: 1). The solvent was evaporated and the residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (20: 1 to 8: 1) to give the title compound (5.08 g).
LC-MS: Rt 3.20 min. Intermediate 66: (4-bromo-2-nitrophenyl) methyl-4-fluorophenyl sulfide

To a solution of 4-bromo-1- (bromomethyl) -2-nitrobenzene (0.60g) in tetrahydrofuran (10ml) was added 4-fluorothiophenol (1.2ml) and diisopropylethylamine (0.45ml). After stirring for 2 h, the mixture was concentrated under vacuum and purified by column chromatography on silica eluted with petroleum ether (40-60 ° C): dichloromethane (9: 1 to 8: 1) to give the title compound (0.52 g). to surrender.
LC-MS: Rt 3.73 min. Intermediate 67: (4-bromo-2-nitrophenyl) methyl-4-fluorophenylsulfone

A suspension of oxone (3.55 g) in water (8 ml) was added to a solution of (4-bromo-2-nitrophenyl) methyl-4-fluorophenyl sulfide (interm. 66) (0.52 g) in acetonitrile (10 ml ) added. The mixture was stirred for 5 h, filtered, and the residue was washed with ethyl acetate. The biphasic filtrate was separated, the aqueous layer back extracted with ethyl acetate (2 x 50 mL) and the combined organic extracts washed with aqueous sodium metabisulfite (5%, 100 mL) and brine. The dried (MgSO ₄ ) extracts were concentrated under vacuum to give the title compound (0.56 g).
LC-MS: Rt 3.33 min. Intermediate 68: (5-bromo-2 - {[(4-fluorophenyl) sulfonyl] methyl} phenyl) amine

Saturated ammonium chloride (2.2 ml) and iron powder (0.25 g) were added to a suspension of (5-bromo-2 - {[(4-fluorophenyl) sulfonyl] methyl} phenyl) amine (interm. 67) (0.56 g) in toluene (10 ml), then stirred at reflux for 18 h. The mixture was cooled and evaporated to give a white solid, which was partitioned between ethyl acetate (3 x 20 mL) and saturated aqueous sodium bicarbonate (15 mL). The dried (MgSO ₄ ) organic extracts were concentrated under vacuum to give the title compound (0.42 g).
LC-MS: Rt 3.16 min. Intermediate 69: (5-bromo-3 - {[(4-fluorophenyl) sulfonyl-1H-indazole

To a suspension of (5-bromo-2 - {[(4-fluorophenyl) sulfonyl] methyl} phenyl) amine (interm. 68) (0.42g) in chloroform (10ml) was added potassium acetate (135g) and acetic anhydride ( 0.24 ml). The mixture was heated under nitrogen at reflux for 18 h. 18-Crown-6 (0.64 g) and tert -butylnitrite (0.435 ml) were added and the mixture was stirred at reflux for a further 42 h. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (4: 1) to give the title compound (0.16 g).
LC-MS: Rt 3.43 min. Intermediate 70: 6-bromo-3 - [(4-fluorophenyl) sulfonyl] -1- ({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indazole

Sodium tert-butoxide (35 g) was added to an ice-cold solution of 6-bromo-3 - [(4-fluorophenyl) sulfonyl] -1H-indazole (interm. 69) (0.11 g) in tetrahydrofuran (1.5 ml ) added. 2- (Trimethylsilyl) ethoxymethyl chloride (0.06 ml) was then added and the mixture was warmed to room temperature over one hour. The reaction was quenched using 2M aqueous ammonia (1 ml) and methanol (1 ml), the solvent was evaporated and the residue was passed through a Varian Bond flood SPE cartridge eluted with cyclohexane: dichloromethane (100: 0 to 0: 100) to give the title compound (0.67 g).
LC-MS: Rt 4.09 min. Intermediate 71: N-Cyclopropyl-3- [3 -] [(4-fluorophenyl) sulfonyl] -1 - ({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indazol-6-yl] -4- methylbenzamide

A mixture of 6-bromo-3 - [(4-fluorophenyl) sulfonyl] -1- ({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indazole (interm. 70) (0.06 g), N -Cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (Intermediate 5) (0.04 g), aqueous sodium carbonate (1M, 0 , 66 ml) and tetrakis (triphenylphosphine) palladium (0) (0.015 g) in 1,2-dimethoxyethane (4 ml) was stirred at reflux under nitrogen for 18 h. The mixture was concentrated under vacuum and the residue was purified via a Varian Bond flood SPE cartridge eluted with cyclohexane: ethyl acetate (100: 0 to 50: 5) to give the title compound (0.05 g).
LC-MS: Rt 3.91 min. Intermediate 72: (4-bromo-2-nitrophenyl) methylmethyl sulfide

A suspension of 4-bromo-1- (bromomethyl) -2-nitrobenzene (1.0 g) and sodium methanethiolate (0.285 g) in tetrahydrofuran (20 ml) was stirred under nitrogen for 60 h. The solvent was evaporated, chloroform (50 ml) was added and the residual solid was removed by filtration. The filtrate was concentrated under vacuum to give the title compound (0.89 g).
LC-MS: Rt 3.35 min. Intermediate 73: (4-bromo-2-nitrophenyl) methylmethylsulfone

A suspension of oxone (7.94g) in water (16ml) was added to a solution of (4-bromo-2-nitrophenyl) methylmethylsulfide (intermediate 72) (0.52g) in acetonitrile (20ml). The mixture was stirred for 5 h, filtered, and the residue was washed with ethyl acetate. The biphasic filtrate was separated, the aqueous layer back extracted with ethyl acetate (2 x 50 mL) and the combined organic extracts washed with aqueous sodium metabisulfite (5%, 100 mL), water and brine. The solution was dried using a hydrophobic filter bag, then concentrated under vacuum to give the title compound (0.35 g).
LC-MS: Rt 2.72 min. Intermediate 74: {5-bromo-2 - [(methylsulfonyl) methyl] phenyl} amine

Tin (II) chloride dihydrate (1.34g) was added to a stirred suspension of (4-bromo-2-nitrophenyl) methylmethylsulfone (interm. 73) in dry ethanol (10ml) and the mixture was allowed to sit at 50 ° C Nitrogen stirred for 2.5 h. The solvent was evaporated and the residue was partitioned between aqueous sodium hydroxide (2M, 30 ml) and dichloromethane (200 ml). The organic phase was dried using a hydrophobic filter bag and concentrated under vacuum to give the title compound (0.26 g).
LC-MS: Rt 2.42 min. Intermediate 75: 6-bromo-3- (methylsulfonyl) -1H-indazole

To a suspension of {5-bromo-2 - [(methylsulfonyl) methyl] phenyl} amine (interm. 74) (0.26g) in chloroform (8ml) was added potassium acetate (0.11g) and acetic anhydride (0.195ml). added. The mixture was heated under nitrogen at reflux for 18 h. 18-Crown-6 (0.26 g) and tert -butylnitrite (0.35 ml) were added and the mixture was stirred at reflux for an additional 88 hours. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (4: 1 to 1: 1) to give the title compound (0.14 g).
LC-MS: Rt 2.85 min. Intermediate 76: 6-bromo-3- (methylsulfonyl) -1 - ({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indazole

Sodium tert -butoxide (0.057 g) was added to an ice-cold solution of 6-bromo-3- (methylsulfonyl) -1H-indazole (Intermediate 75) (0.14 g) in tetrahydrofuran (1.5 ml). 2- (Trimethylsilyl) ethoxymethyl chloride (0.11 ml) was then added and the mixture was warmed to room temperature over 1 h. The reaction was quenched using 2M aqueous ammonia (1 ml) and methanol (1 ml), the solvent was evaporated and the aqueous residue was extracted with ethyl acetate. The organic extracts were dried using a hydrophobic filter bag and concentrated under vacuum to give the title compound (0.67 g).
LC-MS: Rt 3.81 min. Intermediate 77: N-Cyclopropyl-3-fluoro-4-methyl-5- [3- (methylsulfonyl) -1 - ({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indazol-6-yl] benzamide

A mixture of 6-bromo-3- (methylsulfonyl) -1 - ({[2- (trimethylsilyl) ethyloxy} methyl) -1H-indazole (interm. 76) (0.18 g), N-cyclopropyl-3-fluoro 4-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -benzamide (interm. 62) (0.14 g), aqueous sodium carbonate (1M, 1.32 ml ) and tetrakis (triphenylphosphine) palladium (0) (0.01 g) in isopropanol (2 ml) was stirred at reflux under nitrogen for 18 h. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (2: 1) to give the title compound (0.15 g).
LC-MS: Rt 3.82 min. Intermediate 78: 1-acetyl-5-bromo-3-methyl-1H-indazole

A solution of 4-bromo-2-ethylaniline (1.09g) in chloroform (20ml) was stirred at room temperature, then treated with potassium acetate (0.49g), followed by acetic anhydride (0.95ml). 18-crown-6 (0.26 g) and t-butylnitrite (1.32 ml) were added after 30 min, and the mixture was stirred at reflux for 18 h. The reaction mixture was diluted with chloroform and washed with saturated aqueous sodium bicarbonate. The organic phase was separated using a hydrophobic frit and the solvent was evaporated to give the title compound as a brown solid (1.0 g).
NMR: δ H [CDCl ₃ ] 8.30 (1H, d), 7.79 (1H, s), 7.63 (1H, d), 2.74 (3H, s), 2.55 (3H, s ).

General Procedure A

• (A) Tetrakis(triphenylphosphin)palladium (3,5 μmol in 0,1 ml DME) oder
• (B) FibreCat^TM 1001 (12 mg) wurden hinzugegeben, und das Gemisch wurde unter Stickstoff bei 80°C für 18 h erhitzt. Das Reaktionsgemisch wurde
• (A) durch Kieselsäure (100 mg) filtriert und mit Methanol gewaschen,
• (B) durch Celite filtriert und mit DME oder DMF gewaschen.

The halide (30 μmol) was dissolved in DME or DMF (0.4-0.5 ml). The boronate ester (30 .mu.mol in 0.2 ml DME or DMF), sodium carbonate (10% aqueous solution 0.25 ml) and

• (A) Tetrakis (triphenylphosphine) palladium (3.5 μmol in 0.1 ml DME) or
• (B) FibreCat ^™ 1001 (12 mg) was added and the mixture was heated under nitrogen at 80 ° C for 18 h. The reaction mixture was
• (A) filtered through silica (100 mg) and washed with methanol,
• (B) filtered through celite and washed with DME or DMF.

The solvent was evaporated and the residue was dissolved in DMSO (0.25 ml) and by preparative mass-directed LC-MS purified.

General procedure B

A solution of N-cyclopropyl-3- (1H-indazol-5-yl) -4-methylbenzamide (Example 17, 30 mg) in dichloromethane (2 ml) became the sulfonyl chloride (0.11 mmol) was added. Pyridine (50 μmol) was added, and the solution was at 20 ° C for 18 h stirred (if a solution is not produced, a substantial amount of the 2-substituted Formed product). The solvent was evaporated and the residue became by column chromatography on silica, eluted with cyclohexane: ethyl acetate (4: 1 to 1: 1), purified.

General procedure C

A solution of N-cyclopropyl-3- (1H-indazol-5-yl) -4-methylbenzamide (Example 17) or N-cyclopropyl-3-fluoro-5- (1H-indazol-5-yl) -4-methylbenzamide (Example 60) (100 mg) in DMF (3 ml) was treated with sodium hydride (60% Dispersion in oil, 16.5 mg) under nitrogen. After 10 minutes, the sulfonyl chloride became (1.2 equivalents) was added and the suspension was stirred at room temperature for 16 h. methanol (5 ml) was added, the solvent was evaporated and the crude product was purified by column chromatography on silica, eluted with a cyclohexane: ethyl acetate gradient or by preparative purified by reverse phase HPLC.

General procedure D

The solution of the ester methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) or methyl (5- {5 - [(cyclopropylamino) carbonyl] 3-Fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate (Example 123) (0.015g) in methanol (0.2ml) was treated with an amine (3 equivalents), then at 65 ° C stirred under nitrogen for 18 h. The methanol was evaporated and the residue, in chloroform, was applied to a Varian SCX-2 ion exchange column and eluted with chloroform: methanol (9: 1). If required, the product was further purified by preparative reverse phase HPLC. Example 1: N-Cyclopropyl-4-methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) benzamide

Example 1 was prepared by General Procedure A using 6-bromo-3-piperidin-4-yl-1,2-benzixoxazole and Intermediate 5.
NMR: δH [d6-DMSO] 8.43 (1H, s), 8.08 (1H, d), 7.75 (3H, m), 7.43 (2H, t), 3.6 (1H, m), 3,4 (2H, m), 3,12 (2H, m), 2,85 (2H, m), 2,3 (3H, s), 2,2 (2H, m), 2, 1 (2H, m), 0.67 (2H, m), 0.56 (2H, m).
LC-MS: Rt 2.31 min, MH ⁺ 376. Example 2: 4-Methyl-N- (3-morpholin-4-yl-phenyl) -3- (3-piperidin-4-yl-1,2-benzioxazol-6-yl) -benzamide

Example 2 was prepared by General Procedure A using 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole and Intermediate 10.
NMR: δ H [d6-DMSO] 10.09 (1H, s), 8.09 (1H, d), 7.94 (1H, dd), 7.91 (1H, brs), 7.82 (1H, brs), 7.51 (1H, d), 7.47 (1H, d), 7.39 (1H, brs), 7.29 (1H, brd), 7.19 (1H, t), 6, 70 (1H, dd), 3.74 (4H, apparent t), 3.48 (1H, brm), 3.29 (2H, brd), 3.09 (4H, apparent t), 2.95 (2H , brt), 2.34 (3H, s), 2.15 (2H, brd), 2.01 (2H, brt).
LC-MS: Rt 2.56 min, MH ⁺ 497. Example 3: N- [4-Methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) phenyl] -2- pyrrolidin-1-ylisonicotinamid

Example 3 was prepared by General Procedure A using 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole and Intermediate 13.
NMR: δH [d6-DMSO] 10.3 (1H, s), 8.4 (1H, s), 8.2 (1H, d), 8.05 (1H, d), 7.75 (3M, m), 7.4 (1H, d), 7.3 (1H, d), 6.95 (1H, d), 6.85 (1H, s), 3.45 (4M, m), 3, 2 (2M, d), 2.9 (2H, t), 2.25 (3H, s), 2.1 (2H, d), 1.95 (4H, m).
C-MS: Rt 2.26 min, MH ⁺ 482. Example 4: N- [4-Methyl-3- (3-methyl-1,2-benzisoxazol-6-yl) phenyl] -2-rrolidin-1 ylisonicotinamid

A mixture of 6-bromo-3-methyl-1,2-benzisoxazole (11 mg), N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane 2-yl) -phenyl] -2-pyrrolidin-1-yl-isonicotinamide (interm. 13, 15mg) and aqueous sodium carbonate (0.5M, 0.25ml) in anhydrous DME (1ml) was degassed and then under nitrogen touched. A solution of tetrakis (triphenylphosphine) palladium (0) (2.5 mg) in DME (0.25 ml) was added and the mixture was stirred at 80 ° C for 16 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic layer was separated using a hydrophobic filter, the solvent was evaporated, and the residue was purified by column chromatography on silica eluted with a cyclohexane-ethyl acetate gradient to give the title compound as an oil (5.6 mg).
NMR: δH [d6-DMSO, 600 MHz] 10.3 (1H, br s), 8.18 (1H, d), 7.93 (1H, d), 7.74 (1H, dd), 7, 71 (1H, d), 7.67 (1H, s), 7.37 (1H, d), 7.37 (1H, d), 6.97 (1H, d), 6.86 (1H, s ), 3.43 (4H, br t), 2.60 (3H, s), 2.22 (3H, s), 1.96 (4H, br t).
LC-MS: Rt 2.94 min, MH ⁺ 413. Example 5: N- [4-Methyl-3- (3-methyl-1,2-benzisoxazol-6-yl) phenyl] thiophene-3-carboxamide

Example 5 was carried out in the same manner as Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -3-thiophenamide (intermediate 15, 17 mg) was prepared to give an oil (8.5 mg).
NMR: δH [d6-DMSO, 600 MHz] 10.06 (1H, br s), 8.32 (1H, dd), 7.93 (1H, d), 7.73 (1H, dd), 7, 69 (1H, d), 7.67 (1H, br s), 7.64 (1H, dd), 7.62 (1H, dd), 7.37 (1H, dd), 7.31 (1H, d), 2.60 (3H, s), 2.21 (3H, s).
LC-MS: Rt 3.51 min, MH ⁺ 349. Example 6: N- [4-Methyl-3- (3-methyl-1,2-benzisoxazol-6-yl) phenyl] -3-furamide

Example 6 was carried out in the same manner as Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -3-furamide (intermediate 17, 16 mg) to afford the title compound as an oil (8.6 mg).
LC-MS: Rt 3.39 min, MH ⁺ 333. Example 7: 4-Methyl-3- (3-methyl-1,2-benzisoxazol-6-yl) -N- (3-morpholin-4-yl-phenyl) -benzamide

Example 7 was carried out in the same manner as Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and 4-methyl-N- (3-morpholin-4-yl-phenyl) -3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (Intermediate 9, 21 mg) to afford the title compound as an oil (9.6 mg).
NMR: δH [d6-DMSO, 600 MHz] 10.07 (1H, br s), 7.96-7.88 (3H, m), 7.76 (1H, s), 7.50 (1H, d ), 7.46 (1H, d), 7.38 (1H, br s), 7.28 (1H, br d), 7.18 (1H, t), 6.70 (1H, dd), 3 , 74 (4H, m), 2.60 (3H, s), 2.32 (3H, s). LC-MS: Rt 3.47 min, MH ⁺ 428. Example 8: 4-Methyl-3- (3-methyl-1,2-benzisoxazol-6-yl) -N- (1,3-thiazole-2-one) yl) benzamide

Example 8 was carried out in a manner similar to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N- (thiazol-2-yl) -4-methyl-3- (4,4 , 5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (Intermediate 18, 17 mg), followed by purification by mass-directed "autoprep" to afford the title compound as an oil (1, 3 mg).
LC-MS: Rt 3.45 min, MH + 350. Example 9: N-Cyclopropyl-4-methyl-3- (3-methyl-1,2-benzisoxazol-6-yl) benzamide

Example 9 was conducted in a manner similar to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzamide (Intermediate 5, 15mg) was prepared to give the title compound as an oil (8.5mg).
NMR: δH [d6-DMSO, 600 MHz] 8.43 (1H, br d), 7.92 (1H, d), 7.78 (1H, dd), 7.74 (1H, d), 7, 70 (1H, s), 7.42-7.37 (2H, 2xd), 2.85 (1H, m), 2.60 (3H, s), 2.27 (3H, s), 0.67 (2H, m), 0.55 (2H, m).
LC-MS: Rt 3.19 min, MH + 307. Example 10: N- [4-Methyl-3- (3-methyl-1,2-benzisoxazol-5-yl) phenyl] -2-pyrrolidin-1-ylisonicotinamide

Example 10 was carried out in the same manner as Example 4 using 5-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N- [4-methyl-3- (4,4,5,5-tetramethyl] 1,3,2] dioxaborolan-2-yl) -phenyl] -2-pyrrolidin-1-ylisonicotinamide (Intermediate 13, 16 mg) to afford the title compound as an oil (6,6).
LC-MS: Rt 2.91 min, MH + 413. Example 11: N-Cyclopropyl-3- [3 - ({[2-hydroxy-1- (hydroxymethyl) ethyl] amino} methyl) -1,2-benzisoxazole 6-yl] -4-methylbenzamide

A mixture of 2 - [(6-bromo-1,2-benzisoxazol-3-yl) methyl] amino-1,3-propanediol (intermediate 2, 8 mg), N-cyclopropyl-4-methyl-3- (4 , 4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (intermediate 5, 10 mg), aqueous sodium carbonate (1M, 0.1 ml) and tetrakis (triphenylphosphine) palladium (0 ) (1 mg) in 2-propanol (0.2 ml) was stirred at 80 ° C under nitrogen for 18 h. The solvent was evaporated and the residue was purified on a Varian Bond Flood SPE cartridge (silica, 500 mg) using a dichloromethane-methanol elution gradient (19: 1 to 9: 1) to give the title compound as an oil (3 mg).
NMR: δH [d6-DMSO] 8.43 (1H, br d), 8.08 (1H, d), 7.80 (1H, dd), 7.75 (1H, d), 7.73 (1H , br s), 7.40 (2H, 2xd), 4.48 (2H, br t), 4.24 (2H, s), 3.42 (4H, m), 2.85 (1H, m) , 2.61 (1H, m), 2.28 (3H, s), 0.72-0.53 (4H, m).
LC-MS: Rt 2.15 min, MH + 396. Example 12: N- (3-Methoxyphenyl) -4-methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) -benzamide

N- (3-methoxyphenyl) -4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzamide (interm. 19, 54 mg), DME ( 3 ml), aqueous sodium carbonate (1M, 2 ml), tetrakis (triphenylphosphine) palladium (20 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (44 mg) were combined at 80 ° C heated under nitrogen for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica (10 g), eluted with dichloromethane: ethanol: ammonia (40: 8: 1), to give the title compound (37 mg).
NMR: δH [d6-DMSO] 8.05 (1H, d), 7.88-7.97 (2H, m), 7.79 (1H, s), 7.50 (1H, d), 7, 42-7.47 (2H, m), 7.36 (1H, br d), 7.23 (1H, dd), 6.67 (1H, dd), 3.09-3.14 (5H, m ), 2.76 (2H, m), 2.32 (3H, s), 1.99 (2H, m), 1.83 (2H, m).
LC-MS: Rt 2.66 min, MH + 442. Example 13: 4-Methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) -N- (1,3,4 thiadiazol-2-yl) benzamide

4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiadiazol-2-yl) -benzamide (intermediate 20.50.7 mg ), DME (3 ml), aqueous sodium carbonate (1M, 2 ml), tetrakis (triphenylphosphine) palladium (20 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (44 mg) were combined heated at 80 ° C under nitrogen for 18 h. The mixture was evaporated and the residue was purified by column chromatography on silica (10 g) eluted with cyclohexane: ethyl acetate (8: 1 to 1: 1) followed by dichloromethane: ethanol: ammonia (20: 8: 1). to give the title compound (30.1 mg).
NMR: δH [d6-DMSO] 8.95 (1H, s), 8.01-8.09 (4H, m), 7.80 (1H, s), 7.47 (1H, d), 7, 45 (1H, d), 3.25-4.47 (3H, m), 2.97 (2H, dd), 2.32 (3H, s), 2.14 (2H, m), 1.97 (2H, m).
LC-MS: Rt 2.44 min, MH + 420. Example 14: N- [4-Methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) phenyl] thiophene-3-carboxamide

N- [4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] thiophene-3-amide (Intermediate 15, 50 mg), DMF (1.5 ml), aqueous sodium carbonate (1M, 0.75 ml), tetrakis (triphenylphosphine) palladium (7.5 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (41 mg ) were heated together at 80 ° C under nitrogen for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica (10 g), eluted with dichloromethane: ethanol: ammonia (100: 8: 1), to give the title compound (36.8 mg).
NMR: δH [d6-DMSO] 10.07 (1H, d), 8.32 (1H, s), 8.00 (1H, dd), 7.59-7.74 (4H, m), 7, 35 (1H, d), 7.29 (1H, dd), 6.94 (1H, d), 3.02 (2H, m), 2.66 (2H, m), 2.20 (3H, s ), 1.96 (1H, m), 1.78 (2H, m), 1.50 (1H, m).
LC-MS: Rt 2.71 min, MH ⁺ 418. Example 15: N- [4-Methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) -phenyl] -3- furamide

N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -3-furamide (intermediate 17, 47 mg), DMF ( 1.5 ml), aqueous sodium carbonate (1M, 0.75 ml), tetrakis (triphenylphosphine) palladium (7.5 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (41 mg). were heated together at 80 ° C under nitrogen for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica (10 g), eluted with dichloromethane: ethanol: ammonia (100: 8: 1), to give the title compound (37.8 mg).
NMR: δH [d6-DMSO] 9.93 (1H, d), 8.35 (1H, s), 8.00 (1H, dd), 7.78 (1H, s), 7.61-7, 69 (2H, m), 7.35 (1H, d), 7.28 (1H, dd), 6.98 (1H, s), 3.02 (2H, m), 2.65 (2H, m ), 2.21 (3H, s), 1.96 (1H, m), 1.77 (2H, m), 1.49 (1H, m).
LC-MS: Rt 2.55 min, MH + 402. Example 16: N- (Cyclopropylmethyl) -4-methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) benzamide

N-cyclopropylmethyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl) -benzamide (interm. 21, 100mg), DME (5mL), Aqueous sodium carbonate (1M, 3 ml), tetrakis (triphenylphosphine) palladium (0) (37 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (76 mg) were combined together at 80 ° C Nitrogen heated for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica (10 g), eluted with dichloromethane: ethanol: ammonia (100: 8: 1 to 70: 8: 1), to give the title compound (53 mg) ,
NMR: δH [d6-DMSO] 8.56 (1H, t), 8.03 (1H, d), 7.81 (1H, dd), 7.78 (1H, s), 7.74 (1H, s), 7.42 (1H, d), 7.38 (1H, d), 3.12 (2H, t), 3.05 (2H, m), 2.68 (2H, m), 2, 29 (3H, s), 1.95 (2H, m), 1.78 (2H, m), 1.00 (1H, m), 0.41 (2H, m), 0.20 (2H, m ).
LC-MS: Rt 2.56 min, MH + 390. Example 17: N-Cyclopropyl-3- (1H-indazol-5-yl) -4-methylbenzamide

To a solution of tert -butyl-5-bromo-1H-indazole-1-carboxylate (intermediate 3, 2.0 g) and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzamide (Intermediate 5, 2.04g) in DME (125mL) was added tetrakis (triphenylphosphine) palladium (0.78g) and aqueous sodium carbonate (1M, 80mL ) added. The mixture was heated at reflux under nitrogen for 18 h. The solvent was evaporated and the skirt was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (2: 1 to 1: 1) to give the title compound (1.38 g).
NMR: δ H [CDCl ₃ ] 8.10 (1H, s), 7.31-7.68 (7H, m), 6.26 (1H, br s), 2.89 (1H, m), 2, 29 (3H, s), 0.86 (2H, m), 0.60 (2H, m).
LC-MS: Rt 2.82 min, MH + 292. Example 18: N-Cyclopropyl-4-methyl-3- [1- (phenylsulfonyl) -1H-indazol-5-yl] benzamide

Example 18 was prepared by General Procedure B using benzenesulfonyl chloride to give the title compound (10.4 mg).
NMR: δH [d6-DMSO] 8.58 (1H, d), 8.38 (1H, d), 8.19 (1H, d), 7.97 (2H, d), 7.85 (1H, s), 7.62-7.77 (6H, m), 7.39 (1H, d), 2.82 (1H, m), 2.24 (3H, s), 0.65 (2H, m ), 0.53 (2H, m).
LC-MS: Rt 3.37 min, MH + 432. Example 19: N-Cyclopropyl-3- {1 - [(3-fluorophenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide

Example 19 was prepared by General Procedure B using 3-fluorobenzenesulfonyl chloride to give the title compound (19.2 mg).
NMR: δH [d6-DMSO] 8.62 (1H, s), 8.38 (1H, d), 8.20 (1H, d), 7.86 (1H, s), 7.60-7, 84 (7H, m), 7.39 (1H, d), 2.82 (1H, m), 2.24 (3H, s), 0.65 (2H, m), 0.53 (2H, m ).
LC-MS: Rt 3.44 min, MH ⁺ 450. Example 20: 3- {1 - [(3-Cyanophenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-4-methylbenzamide

Example 20 was prepared by General Procedure B using 3-cyanobenzenesulfonyl chloride to give the title compound (14.5 mg).
NMR: δH [d6-DMSO] 8.64 (1H, s), 8.51 (1H, s), 8.39 (1H, d), 8.27 (1H, d), 8.21-8, 24 (2H, m), 7.87 (1H, s), 7.83 (1H, dd), 7.76 (1H, d), 7.68-7.72 (2H, m), 7.39 (1H, d), 2.82 (1H, m), 2.24 (3H, s), 0.65 (2H, m), 0.51 (2H, m).
LC-MS: Rt 3.34 min, MH ⁺ 457. Example 21: N-Cyclopropyl-3- {1 - [(3,4-difluorophenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide

Example 21 was prepared by General Procedure B using 3,4-difluorobenzenesulfonyl chloride to give the title compound (15.6 mg).
NMR: δ H [d6-DMSO] 8.63 (1H, s), 8.40 (1H, br d), 8.21 (1H, d), 8.16 (1H, td), 7.85-7 , 90 (2H, m), 7.65-7.80 (4H, m), 7.40 (1H, d), 2.82 (1H, m), 2.25 (3H, s), 0, 67 (2H, m), 0.54 (2H, m).
LC-MS: Rt 3.49 min, MH ⁺ 468. Example 22: N-Cyclopropyl-4-methyl-3- [1- (methylsulfonyl) -1H-indazol-5-yl] -benzamide

Example 22 was prepared by General Procedure B using methanesulfonyl chloride to give the title compound (6.9 mg).
NMR: δH [d6-DMSO] 8.64 (1H, s), 8.42 (1H, d), 8.03 (1H, d), 7.91 (1H, s), 7.76 (1H, d), 7.73 (1H, s), 7.66 (1H, dd), 7.40 (1H, d), 3.50 (3H, s), 2.84 (1H, m), 2, 28 (3H, s), 0.67 (2H, m), 0.55 (2H, m).
LC-MS: Rt 2.97 min, MH ⁺ 370. Example 23: N-Cyclopropyl-3- [1- (2,3-dihydro-1-benzofuran-5-ylsulfonyl) -1H-indazol-5-yl] -4-methylbenzamide

Example 23 was prepared by General Procedure B using 2,3-dihydro-1-benzofuran-5-sulfonyl chloride to give the title compound (9.2 mg).
NMR: δH [d6-DMSO] 8.54 (1H, s), 8.39 (1H, d), 8.17 (1H, d), 7.82-7.86 (2H, m), 7, 74-7.77 (2H, m), 7.70 (1H, br s), 7.66 (1H, dd), 7.39 (1H, d), 6.93 (1H, d), 4, 62 (2H, dd), 3.21 (2H, dd), 2.83 (1H, m), 2.25 (3H, s), 0.66 (2H, m), 0.54 (2H, m ).
MS: e / z + 474. Example 24: N-Cyclopropyl-3- {1 - [(3-methoxyphenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide

Example 24 was prepared by general procedure B using 3-methoxyphenylsulfonyl chloride to give the title compound (11.0 mg).
NMR: δH [d6-DMSO] 8.59 (1H, s), 8.39 (1H, d), 8.19 (1H, d), 7.85 (1H, s), 7.76 (1H, d), 7.65-7.73 (2H, m), 7.49-7.54 (2H, m), 7.37-7.41 (2H, m), 7.30 (1H, d) , 3.78 (3H, s), 2.82 (1H, m), 2.24 (3H, s), 0.66 (2H, m), 0.53 (2H, m).
LC-MS: Rt 3.42 min, MH ⁺ 462. Example 25: 3- [1-Benzylsulfonyl) -1H-indazol-5-yl] -N-cyclopropyl-4-methylbenzamide

Example 25 was prepared by General Procedure B using benzylsulfonyl chloride to give the title compound (16.4 mg).
NMR: δH [d6-DMSO] 8.64 (1H, s), 8.41 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.67 (1H, d), 7.51 (1H, d), 7.37 (1H, dd), 7.18 (1H, dd), 7.12 (2H, dd), 7.00 (2H, d), 5, 02 (3H, s), 2.83 (1H, m), 2.21 (3H, s), 0.67 (2H, m), 0.54 (2H, m).
LC-MS: Rt 3.34 min, MH ⁺ 446. Example 26: N-Cyclopropyl-3- {1 - [(5-isoxazol-3-ylienien-2-yl) sulfonyl] -1H-indazole-5- yl} -4-methylbenzamide

Example 26 was prepared by General Procedure B using 5-isoxazol-3-ylthiophene-2-sulfonyl chloride to give the title compound (3.5 mg).
NMR: δH [d6-DMSO] 8.73 (1H, s), 8.70 (1H, s), 8.39 (1H, d), 8.16 (1H, d), 8.03 (1H, d), 7.90 (1H, s), 7.69-7.79 (4H, m), 7.39 (1H, d), 7.16 (1H, d), 2.83 (1H, m ), 2.25 (3H, s), 0.66 (2H, m), 0.52 (2H, m).
LC-MS: Rt 3.46 min, MH ⁺ 505. Example 27: 3- {1 - [(4-Acetylphenyl) sulfonyl] 1H-indazol-5-yl} -N-cyclopropyl-4-methylbenzamide

Example 27 was prepared by General Procedure B using 4-acetylphenylsulfonyl chloride to give the title compound (3.6 mg).
NMR: δ H [d6-DMSO] 8.62 (1H, s), 8.38 (1H, d), 8.21 (1H, d), 8.10 (4H, m), 7.86 (1H, s), 7.76 (1H, dd), 7.69-7.71 (2H, m), 7.39 (1H, d), 2.83 (1H, m), 2.57 (3H, s ), 2.24 (3H, s), 0.66 (2H, m), 0.52 (2H, m).
LC-MS: Rt 3.32 min, MH ⁺ 474. Example 28: Methyl 4 - {[(5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) sulfonyl ] methyl} benzoate

Example 28 was prepared by General Procedure B using methyl 4 - [(chlorosulfonyl) methyl] benzoate to give the title compound (7.8 mg).
NMR: δH [d6-DMSO] 8.64 (1H, s), 8.39 (1H, d), 7.78 (1H, s), 7.74 (1H, d), 7.66 (2H, d), 7.64 (1H, s), 7.45 (1H, d), 7.37 (1H, d), 7.31 (1H, d), 7.11 (2H, d), 5, 17 (2H, s), 3.76 (3H, s), 2.83 (1H, m), 2.13 (3H, s), 0.67 (2H, m), 0.54 (2H, m ).
LC-MS: Rt 3.38 min, MH ⁺ 504. Example 29: N-Cyclopropyl-3- {1 - [(3,4-dimethoxyphenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide

Example 29 was prepared by General Procedure B using 3,4-dimethoxybenzenesulfonyl chloride to give the title compound (4.2 mg).
NMR: δH [d6-DMSO] 8.56 (1H, s), 8.39 (1H, d), 8.20 (1H, d), 7.84 (1H, s), 7.75 (1H, d), 7.70 (1H, s), 7.66 (1H, d), 7.57 (1H, dd), 7.39 (1H, d), 7.35 (1H, d), 7, 14 (1H, d), 3.80 (3H, s), 3.77 (3H, s), 2.83 (1H, m), 2.24 (3H, s), 0.65 (2H, m ), 0.53 (2H, m).
LC-MS: Rt 3.29 min, MH ⁺ 492. Example 30: N-Cyclopropyl-4-methyl-3- (1 - {[4- (trifluoromethyl) -phenyl] sulfonyl} -1H-indazol-5-yl ) benzamide

Example 30 was prepared by General Procedure B using 4- (trifluoromethyl) benzenesulfonyl chloride to give the title compound (13.3 mg).
NMR: δH [d6-DMSO] 8.64 (1H, s), 8.39 (1H, d), 8.17-8.23 (3H, m), 8.02 (2H, d), 7, 87 (1H, s), 7.76 (1H, d), 7.71 (1H, d), 7.70 (1H, s), 7.39 (1H, d), 2.83 (1H, m ), 2.24 (3H, s), 0.65 (2H, m), 0.53 (2H, m).
LC-MS: Rt 3.61 min, MH ⁺ 500. methylbenzamide Example 31: N-Cyclopropyl-3- {1 - [(4-fluorophenyl) sulfonyl] -1H-indazol-5-yl} -4-

Example 31 was prepared by General Procedure B using 4-fluorobenzenesulfonyl chloride to give the title compound (13.3 mg).
NMR: δ H [d6-DMSO] 8.39 (1H, s), 8.25 (1H, d), 8.06 (2H, dd), 7.76 (1H, s), 7.71 (1H, d), 7.66 (1H, s), 7.62 (1H, d), 7.38 (1H, d), 7.29 (2H, dd), 2.82 (1H, m), 2, 27 (3H, s), 0.78 (2H, m), 0.61 (2H, m).
LC-MS: Rt 3.41 min, MH ⁺ 450. Example 32: 4-Methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) -N- (1,3- thiazol-2-yl) benzamide

4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiazol-2-yl) -benzamide (Intermediate 18, 50 mg) DME (3 ml), aqueous sodium carbonate (1M, 2 ml), tetrakis (triphenylphosphine) palladium (20 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (44 mg, 147 μmol) were combined heated at 80 ° C under nitrogen for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica (10 g), eluted with dichloromethane: ethanol: ammonia (100: 8: 1), to give the title compound (43 mg).
NMR: δH [d6-DMSO] 8.00-8.09 (3H, m), 7.81 (1H, s), 7.44-7.52 (3H, m), 7.19 (1H, d ), 3.08 (2H, m), 2.69 (2H, m), 2.34 (3H, s), 1.98 (2H, m), 1.80 (2H, m). Example 33: N-Cyclopropyl-4-methyl-3- [3- (1-piperazinyl) -1,2-benzisoxazol-6-yl] benzamide

A solution of 1,1-dimethyl-4- (6- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1,2-benzisoxazol-3-yl) -1-piperazinecarboxylate (interm. 26) in methanol ( 1 ml) was treated with a solution of hydrogen chloride in dioxane (4N, 1 ml), then stirred at room temperature for 18 h. The solvent was evaporated and the residue was redissolved in methanol and applied to an SCX cartridge (1 g). Elution with methanol followed by methanol: 0.88 ammonia (99: 1) gave the title compound as a white solid (0.016 g).
LC-MS: Rt 2.31 min, MH + 377. Example 34: N-Cyclopropyl-4-methyl-3- [3- (4-morpholinyl) -1,2-benzisoxazol-6-yl] benzamide

A mixture of 6-bromo-3- (4-morpholinyl) -1,2-benzisoxazole (interm. 27) (0.016 g), N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl) 1,3,2-dioxaborolan-2-yl) benzamide (interm. 5), (0.03g), 2N aqueous sodium carbonate (1ml) and tetrakis (triphenylphosphine) palladium (0) (0.5mg) in isopropanol ( 3 ml) was stirred at reflux under nitrogen for 17 h. The residue was absorbed onto silica (Merck 7734) and applied to a Varian Bond Flood SPE cartridge (silica, 5 g). Elution with dichloromethane: methanol (98: 2) gave the title compound as a white solid (0.024 g).
LC-MS: Rt 3.03 min, MH + 378. Example 35: N-Cyclopropyl-4-methyl-3- {3- [2-oxo-2- (1-piperazinyl) ethyl] -1,2-benzisoxazole -6-yl} benzamide Example 36: Methyl (6- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1,2-benzisoxazol-3-yl) acetate

A suspension of 1,1-dimethylethyl 4 - [(6- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1,2-benzisoxazol-3-yl) acetyl] -1-piperazinecarboxylate (interm. 34 ) (0.03 g) in methanol (1 ml) de with a solution of hydrogen chloride in dioxane (4M, 1 ml) to give a colorless solution which was stirred at room temperature for 18 h. The solvent was evaporated and the residue was partitioned between dichloromethane (2 ml) and 2M aqueous sodium carbonate (2 ml). The organic layer was applied to a Varian Bond flood SPE cartridge (silica, 5 g) and sequentially eluted with dichloromethane, ether, ethyl acetate, acetonitrile, acetone, dichloromethane: ethanol: 0.88 ammonia (100: 8: 1), Dichloromethane: ethanol: 0.88 ammonia (40: 8: 1), ethanol and methanol to give Example 35 (6 mg) as a white solid and Example 36 (4 mg) as a white solid.
Example 35 - LC-MS: Rt 2.27 min, MH + 19.
Example 36 - LC-MS: Rt 3.02 min, MH + 365. Example 37: N-Cyclopropyl-3- (3- {2 - [(2-hydroxyethyl) amino] -2-oxoethyl} -1,2-benzisoxazole -6-yl) -4-methylbenzamide

A mixture of N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (interm. 5) (0.04 g), 2- (6-bromo-1,2-benzisoxazol-3-yl) -N- (2-hydroxyethyl) acetamide (interm. 35) (0.04g), 2M aqueous sodium carbonate (1.5ml) and tetrakis (triphenylphosphine) palladium (0) (1 mg) in isopropanol (3 ml) was stirred at reflux under nitrogen for 18 h. The mixture was absorbed onto silica (Merck 7734) and applied to a Varian Bond flood SPE cartridge (silica, 5 g) and eluted with a toluene: ethanol gradient (100: 0 to 0: 100) to give the title compound as a white solid (0.03 g).
LC-MS: Rt 2.60 min, MH + 394. Example 38: N-Cyclopropyl-4-methyl-3- {3- [2-oxo-2- (1-piperidinyl) ethyl] -1,2-benzisoxazole -6-yl} benzamide

The procedure for Example 37 was followed using 6-bromo-3- [2-oxo-2- (1-piperidinyl) ethyl] -1,2-benzisoxazole (Intermediate 36) (0.04 g) instead of Intermediate 35 to give the title compound as a white solid (0.03 g).
LC-MS: Rt 3.10 min, MH + 418. Example 39: N-Cyclopropyl-4-methyl-3- {3- [2- (methylamino) -2-oxoethyl] -1,2-benzisoxazol-6-yl} benzamide

The procedure for Example 37 was followed using 2- (6-bromo-1,2-benzisoxazol-3-yl) -N-methylacetamide (interm. 37) (0.04 g) in place of intermediate 35 to afford the title compound as to give a white solid (0.02 g).
LC-MS: Rt 2.69 min, MH + 364. Example 40: N-Cyclopropyl-3- (3- {2 - [(3-hydroxypropyl) amino] -2-oxoethyl} -1,2-benzisoxazole-6- yl) -4-methylbenzamide

The procedure for Example 37 was followed using 2- (6-bromo-1,2-benzisoxazol-3-yl) -N- (3-hydroxypropyl) acetamide (Intermediate 38) (0.04 g) instead of Intermediate 35 to give the title compound as a white solid (0.03 g).
LC-MS: Rt 2.60 min, MH + 408. Example 41: N-Cyclopropyl-3- (3- {2 - [(cyclopropylmethyl) amino] -2-oxoethyl} -1,2-benzisoxazol-6-yl) -4-methylbenzamide

The procedure for Example 37 was followed using 2- (6-bromo-1,2-benzisoxazol-3-yl) -N- (cyclopropylmethyl) acetamide (Intermediate 39) (0.04 g) in place of Intermediate 35 to give to give the title compound as a white solid (0.02 g).
LC-MS: Rt 2.99 min, MH + 404. Example 42: N-Cyclopropyl-4-methyl-3- {3- [2-oxo-2- (1-pyrrolidinyl) ethyl] -1,2-benzisoxazol-6-yl} benzamide

The procedure for Example 37 was followed using 6-bromo-3- [2-oxo-2- (1-pyrrolidinyl) ethyl] -1,2-benzisoxazole (Intermediate 40) (0.04 g) instead of Intermediate 35 to give the title compound as a white solid (0.01 g).
LC-MS: Rt 3.19 min, MH + 404. Example 43: N-Cyclopropyl-3- {3- [2- (ethylamino) -2-oxoethyl] -1,2-benzisoxazol-6-yl} -4- methylbenzamide

The procedure for Example 37 was followed using 2- (6-bromo-1,2-benzisoxazol-3-yl) -N-ethylacetamide (Intermediate 41) (0.04 g) in place of Intermediate 35 to afford the title compound as to give a white solid (0.02 g).
LC-MS: Rt 2.81 min, MH + 378. Example 44: N-Cyclopropyl-3- {3- [2- (cyclopropylamino) -2-oxoethyl] -1,2-benzisoxazol-6-yl} -4- methylbenzamide

The procedure for Example 37 was followed using 2- (6-bromo-1,2-benzisoxazol-3-yl) -N-cyclopropylacetamide (interm. 42) (0.04 g) in place of intermediate 35 to afford the title compound as to give a white solid (0.02 g).
LC-MS: Rt 2.83 min, MH + 390. Example 45: N-Cyclopropyl-4-methyl-3- {3- [2- (4-morpholinyl) -2-oxoethyl] -1,2-benzisoxazol-6-yl} benzamide

The procedure for Example 37 was followed using 6-bromo-3- [2- (4-morpholinyl) -2-oxoethyl] -1,2-benzisoxazole (Intermediate 43) (0.04 g) instead of Intermediate 35, to give the title compound as a white solid (0.02 g).
LC-MS: Rt 2.79 min, MH + 420. Example 46: N-Cyclopropyl-4-methyl-3- {3- [2 - ({[3- (methyloxy) -phenyl] methyl} amino) -2- oxoethyl] -1,2-benzisoxazol-6-yl} benzamide

The procedure for Example 37 was repeated using 2- (6-bromo-1,2-benzisoxazol-3-yl) - N - {[3- (methyloxy) phenyl] methyl} acetamide (interm. 44) (0.05 g ) instead of intermediate 35 to give the title compound as a white solid (0.02 g).
LC-MS: Rt 3.16 min, MH + 470. Example 47: N-Cyclopropyl-4-methyl-3- {3- [2-oxo-2- (1,3-thiazol-2-ylamino) ethyl} - 1,2-benzisoxazol-6-yl} benzamide

The procedure for Example 37 was repeated using 2- (6-bromo-1,2-benzisoxazol-3-yl) -N-1,3-thiazol-2-ylacetamide (Intermediate 45) (0.03 g) instead of Intermediate 35 followed. The SPE cartridge was eluted with cyclohexane: ethyl acetate (100: 0 to 50:50) to give the title compound as a white solid (0.005 g).
LC-MS: Rt 3.06 min, MH + 433. Example 48: N-Cyclopropyl-4-methyl-3- {3 - [(4-methyl-1-piperazinyl) methyl] -1,2-benzisoxazol-6-yl} benzamide

A mixture of 6-bromo-3 - [(4-methyl-1-piperazinyl) methyl] -1,2-benzisoxazole (interm. 46) (0.02 g), N-cyclopropyl-4-methyl-3- (4 , 4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) benzamide (interm. 5) (0.02g), 2N aqueous sodium carbonate and tetrakis (triphenylphosphine) palladium (0) (1mg) Isopropanol (0.3 ml) was heated in a Reactivial ^™ at 65 ° C for 18 h. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated, and the aqueous phase was back-extracted with ethyl acetate. The combined organic extracts were washed with water (2x) and brine, dried using a hydrophobic filter bag and concentrated under a stream of nitrogen. The residue was purified by preparative reverse phase HPLC to give the title compound as a white foam (0.006 g).
LC-MS: Rt 2.26 min, MH + 405. Example 49: N-Cyclopropyl-4-methyl-3- [3- (1-piperidinylmethyl) -1,2-benzisoxazol-6-yl] benzamide

The procedure for Example 48 was followed using 6-bromo-3- (1-piperidinylmethyl) -1,2-benzisoxazole (interm. 47) (0.015g) instead of intermediate 46 to afford the title compound as a white foam (0.005g ).
LC-MS: Rt 2.28 min, MH + 390. Example 50: N-Cyclopropyl-4-methyl-3- [3- (4-morpholinylmethyl) -1,2-benzisoxazol-6-yl] benzamide

The procedure for Example 48 was followed using 6-bromo-3- (4-morpholinylmethyl) -1,2-benzisoxazole (interm. 48) (0.025g) instead of intermediate 46 to afford the title compound as a white foam (0.002g ).
LC-MS: Rt 2.64 min, MH + 392. Example 51: N-Cyclopropyl-4-methyl-3- [3- (1-pyrrolidinylmethyl) -1,2-benzisoxazol-6-yl] benzamide

The procedure for Example 48 was followed using 6-bromo-3- (1-pyrrolidinylmethyl) -1,2-benzisoxazole (Intermediate 49) (0.015g) instead of Intermediate 46 to afford the title compound as a white foam (0.002g ).
LC-MS: Rt 2.24 min, MH + 376. Example 52: 3- (3-Amino-1,2-benzisoxazol-6-yl) -N-cyclopropyl-4-methylbenzamide

A mixture of 3-amino-6-bromo-1,2-benzisoxazole (0.04 g), N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) benzamide (Intermediate 5) (0.07g) and saturated aqueous sodium bicarbonate (0.25ml) was stirred under nitrogen, treated with tetrakis (triphenylphosphine) palladium (0), then heated at reflux for 6h , Ethyl acetate (2 ml) and water (2 ml) were added to the cooled mixture and the phases were separated. The organic layer was washed with brine, dried using a hydrophobic filter bag and concentrated under a stream of nitrogen. The residue was purified by preparative reverse phase HPLC to give the title compound as a white foam (0.006 g).
LC-MS: Rt 2.75 min, MH + 308. Example 53: N-Cyclopropyl-3- [3- (cyclopropylamino) -1,2-benzisoxazol-6-yl] -5-fluoro-4-methylbenzamide

A mixture of 6-bromo-N-cyclopropyl-1,2-benzisoxazol-3-amine (Intermediate 53) (0.02 g), N-cyclopropyl-3-fluoro-4-methyl-5- (4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (interm. 62) (0.02g), saturated aqueous sodium bicarbonate (0.5ml) and tetrakis (triphenylphosphine) palladium (0) in isopropanol (2 ml) was heated in a microwave at 150 ° for 10 min. The residue was absorbed onto silica (Merck 7734) and applied to a Varian Bond flooding SPE cartridge (silica, 5 g) and eluted with cyclohexane: ethyl acetate (75:25 to 0: 100) to afford the title compound (10 g ).
LC-MS: Rt 3.20 min, MH + 366. Example 54: 6- {5 - [(Cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (cyclopropylmethyl) -1,2-benzisoxazole-3 -carboxamide

A mixture of 6-bromo-N- (cyclopropylmethyl) -1,2-benzisoxazole-3-carboxamide (interm. 56) (0.03 g), N-cyclopropyl-3-fluoro-4-methyl-5- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (interm. 62) (0.03g), saturated aqueous sodium bicarbonate (0.25ml) and tetrakis (triphenylphosphine) palladium (0) (1 mg) in isopropanol (0.5 ml) was stirred under nitrogen for 4 h at reflux. Ethyl acetate (2 ml) and water (2 ml) were added, the phases were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic extracts were washed with brine, dried using a hydrophobic filter bag and concentrated under a stream of nitrogen. The residue was purified on a Varian Bond Elut SPE cartridge (silica, 1 g) and eluted with cyclohexane: ethyl acetate (100: 0 to 50:50) to afford the title compound (0.03 g) as a colorless foam result.
LC-MS: Rt 3.37 min, MH + 408. Example 55: 6- {5 - [(Cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N-propyl-1,2-benzisoxazole-3-carboxamide

The procedure for Example 54 was followed using 6-bromo-N-propyl-1,2-benzisoxazole-3-carboxamide (interm. 57) (0.04 g) instead of intermediate 56 to afford the title compound as a yellow foam ( 0.02 g).
LC-MS: Rt 3.32 min, MH + 396. Example 56: 6- {5 - [(Cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N-methyl-1,2-benzisoxazole-3-carboxamide

The procedure for Example 54 was followed using 6-bromo-N-methyl-1,2-benzisoxazole-3-carboxamide (interm. 58) (0.04 g) in place of intermediate 56 to afford the title compound as a yellow foam ( 0.02 g).
LC-MS: Rt 3.04 min, MH + 368. Example 57: 6- {5 - [(Cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N, N-dimethyl-1,2-benzisoxazole-3 -carboxamide

The procedure for Example 54 was followed using 6-bromo-N, N-dimethyl-1,2-benzisoxazole-3-carboxamide (interm. 59) (0.04 g) in place of intermediate 56 to give the title compound as a yellow To give foam (0.02 g).
LC-MS: Rt 3.05 min, MH + 382. Example 58: N-Cyclopropyl-6- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1,2-benzisoxazole-3-carboxamide

The procedure for Example 54 was followed using 6-bromo-N-cyclopropyl-1,2-benzisoxazole-3-carboxamide (interm. 60) (0.04 g) in place of intermediate 56 to afford the title compound as a yellow foam ( 0.02 g).
LC-MS: Rt 3.18 min, MH + 394. Example 59: 1,1-Dimethylethyl-5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazole-1-carboxylate

A mixture of tert -butyl 5-bromo-1H-imidazole-1-carboxylate (interm. 3) (1.07 g) {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} boronic acid (interm. 64 ) (0.85 g), sodium carbonate (1.9 g) and tetrakis (triphenylphosphine) palladium (0) (0.42 g) in 1,2-dimethoxyethane (70 ml) were stirred at reflux under nitrogen for 20 h. The solvent was removed and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was back-extracted with ethyl acetate (3 x 30 mL) and the combined organic extracts were dried using a hydrophobic filter tube and concentrated under vacuum. The residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (75:25 to 60:40) to give the title compound (3.1 g).
LC-MS: Rt 3.46 min, MH + 410. Example 60: N-Cycloropyl-3-fluoro-5- (1H-indazol-5-yl) -4-methylbenzamide

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 62: N-Chlorpropyl-3-[1-(ethylsulfonyl)-1H-indazol-5-yl]-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 63: N-Cyclopropyl-3-[1-(cyclopropylsulfonyl-1H-indazol-5-yl}-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 64: Methyl-5-[(5-{5-[(cyclopropylamino)carbonyl]-2-methylpenyl}-1H-indazol-1-yl)sulfonyl]-2-furancarboxylat

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 65: 3-[1-(2,1,3-Benzoxazol-4-ylsulfonyl)-1H-indazol-5-yl]-N-cyclopropyl-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 66: N-Cyclopropyl-3-{1-[(2-fluorpenyl)sulfonyl]-1H-indazl-5-yl}-4-metylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 67: N-Cyclopropyl-4-methyl-3-{1-[(4-methylphenyl)sulfonyl]-1-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 68: N-Cyclopropyl-4-methyl-3-[1-(2-thienylsulfonyl)-1H-indazol-5-yl]benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 69: N-Cyclopropyl-3-{1-[(3,5-dimethyl-4-isoxazolyl)sulfonyl-1H-indazol-5-yl}-4-metylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 70: N-Cylopropyl-4-methyl-3-[1-(propylsufonyl)-1H-indazol-5-yl]benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 71: N-Cyclopropyl-4-methyl-3-{1-[(2-nitrophenyl)sulfonyl}-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 72: N-Cyclopropyl-4-methyl-3-{1-[(2,2,2-trifluorethyl)-sulfonyl]-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 73: 3-{1-[(2-Cyanophenyl)sulfonyl]-1H-indazol-5-yl}-N-cyclopropyl-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 74: N-Cyclopropyl-4-methyl-3-{1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 75: N-Cyclopropyl-4-methyl-3-{1-[1-methyl-1H-imidazol-4-yl)sulfonyl]-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 76: N-Cyclopropyl-3-fluor-4-methyl-5-[1-(2-thienylsulfonyl)-1H-indazol-5-yl]benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 77: N-Cyclopropyl-3-fluor-4-methyl-5-[1-(3-thienylsulfonyl)-1H-indazol-5-yl]benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 78: N-Cyclopropyl-3-fluor-4-methyl-5-{1-[(4-methyl-phenyl)sulfonyl]-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 79: N-Cyclopropyl-3-fluor-4-methyl-5-(1-{[4-(methyloxy)-phenyl]sulfonyl}-1H-indazol-5-yl)benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 80: N-Cyclopropyl-3-fluor-4-methyl-5-(1-{[4-(1-methylethyl)-phenyl]sulfonyl}-1H-indazol-5-yl)benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 81: 3-{1-[(4-Chlorphenyl)sulfonyl]-1H-indazol-5-yl}-N- cyclopropyl-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 82: N-Cyclopropyl-3-{1-[(2,4-difluorphenyl)sulfonyl]-1H-indazol-5-yl}-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 83: 3-{1-[(3-Chlorphenyl)sulfonyl]-1H-indazol-5-yl}-N-cyclopropyl-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 84: N-Cyclopropyl-3-fluor-5-{1-[(5-fluor-2-methylphenyl)-sulfonyl]-1H-indazol-5-yl}-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 85: N-Cyclopropyl-3-fluor-5-{1-[(3-fluorphenyl)sulfonyl]-1H-indazol-5-yl}-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 86: N-Cyclopropyl-3-fluor-4-methyl-5-(1-{[3-(methyloxy)-phenyl]sulfonyl}-1H-indazol-5-yl)benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 87: N-Cyclopropyl-3-{1-[(3,5-difluorphenyl)sulfonyl]-1H-indazol-5-yl}-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 88: N-Cyclopropyl-3-fluor-4-methyl-5-{1-[(3-methylphenyl)sulfonyl]-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 89: N-Cyclopropyl-3-fluor-4-methyl-5-{1-[(1-methylethyl)-sulfonyl]-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 90: N-Cyclopropyl-3-fluor-4-methyl-5-[1-(propylsulfonyl)-1H-indazol-5-yl]benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 91: N-Cyclopropyl-3-fluor-4-methyl-5-[1-(methylsulfonyl)-1H-indazol-5-yl]benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 92: 3-[1-(Butylsulfonyl)-1H-indazol-5-yl]-N-cyclopropyl-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 93: N-Cyclopropyl-3-fluor-4-methyl-5-[1-(octylsulfonyl)-1H-indazol-5-yl]benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 94: N-Cyclopropyl-3-[1-(cyclopropylsulfonyl)-1H-indazol-5-yl]-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 95: 3-{1-[(5-Chlor-2-thienyl)sulfonyl]-1H-indazol-5-yl}-N-cyclopropyl-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 96: N-Cyclopropyl-3-{1-[(3,5-dimethyl-4-isoxazolyl)sulfonyl]-1H-indazol-5-yl}-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 97: N-Cyclopropyl-3-{1-[(1,2-dimethyl-1H-imidazol-4-yl)-sulfonyl]-1H-indazol-5-yl}-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 98: N-Cyclopropyl-3-[1-(ethylsulfonyl)-1H-indazol-5-yl]-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 99: 3-{1-[(2-Chlorphenyl)sulfonyl]-1H-indazol-5-yl}-N-cyclopropyl-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 100: N-Cyclopropyl-3-fluor-4-methyl-5-{1-[(2-methylphenyl)-sulfonl]-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 101: N-Cyclopropyl-3-{1-[(4-ethylphenyl)sulfonyl]-1H-indazol-5-yl}-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 102: N-Cyclopropyl-3-fluor-4-methyl-5-{1-[(4-propylphenyl)-sulfonyl]-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 103: N-Cyclopropyl-3-{1-[3,4-difluorphenyl)sulfonyl]-1H-indazol-5-yl}-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 104: 3-{1-[(4-Butylphenyl)sulfonyl]-1H-indazol-5-yl}-N-cyclopropyl-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 105: N-Cyclopropyl-3-fluor-4-methyl-5-[1-(phenylsulfonyl)-1H-indazol-5-yl]benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 106: N-Cyclopropyl-3-fluor-4-methyl-5-{1-[(phenylmethyl)-sulfonyl]-1H-indazol-5-yl}benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 107: N-Cyclopropyl-3-fluor-4-methyl-5-(1-{[(E)-2-phenylethenyl]sulfonyl}-1H-indazol-5-yl)benzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 108: N-Cyclopropyl-3-{1-[(2,5-difluorphenyl)sulfonyl]-1H-indazol-5-yl}-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 109: N-Cyclopropyl-3-fluor-5-{1-[(2-fluorphenyl)sulfonyl]-1H-indazol-5-yl}-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 110: 3-{1-[(4-Cyanophenyl)sulfonyl]-1H-indazol-5-yl}-N-cyclopropyl-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Beispiel 111: N-Cyclopropyl-3-[1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-1H-indazol-5-yl}-5-fluor-4-methylbenzamid

Hergestellt durch das allgemeine Verfahren C. Siehe Tabelle. Tabelle (Beispiele 61-111) Beispiel Nr. Indazol-Vorläufer Sulfonylchlorid Rt (min) MH+ Beispiel 61 Beispiel 17 2-Propansulfonylchlorid¹ 3,17 398 Beispiel 62 Beispiel 17 Ethansulfonylchlorid² 3,13 384 Beispiel 63 Beispiel 17 Cyclopropansulfonylchlorid³ 3,18 396 Beispiel 64 Beispiel 17 Methyl-5-(chlorsulfonyl)-2-furancarboxylat⁴ 3,29 480 Beispiel 65 Beispiel 17 2,1,3-Benzoxadiazol-4-sulfonylchlorid⁴ 3,36 474 Beispiel 66 Beispiel 17 2-Fluorbenzolsulfonylchlorid¹ 3,38 450 Beispiel 67 Beispiel 17 4-Methylbenzolsulfonylchlorid¹ 3,38 446 Beispiel 68 Beispiel 17 2-Thiophensulfonylchlorid¹ 3,33 438 Beispiel 69 Beispiel 17 3,5-Dimethyl-4-isoxazolsulfonylchlorid⁴ 3,38 451 Beispiel 70 Beispiel 17 1-Propansulfonylchlorid5 3,11 398 Beispiel 71 Beispiel 17 2-Nitrobenzolsulfonylchlorid¹ 3,4 477 Beispiel 72 Beispiel 17 2,2,2-Trifluorethansulfonylchlorid¹ 3,11 438 Beispiel 73 Beispiel 17 2-Cyanobenzolsulfonylchlorid¹ 3,31 457 Beispiel 74 Beispiel 17 1,3,5-Trimethyl-1H-pyrazol-4-sulfonylchlorid⁴ 3,18 464 Beispiel 75 Beispiel 17 1-Methyl-1H-imidazol-4-sulfonylchlorid⁴ 2,88 436 Beispiel 76 Beispiel 60 2-Thiophensulfonylchlorid¹ 3,42 456 Beispiel 77 Beispiel 60 3-Thiophensulfonylchlorid⁴ 3,39 456 Beispiel 78 Beispiel 60 4-Methylbenzolsulfonylchlorid¹ 3,57 464 Beispiel 79 Beispiel 60 4-(Methyloxy)benzolsulfonylchlorid² 3,5 480 Beispiel 80 Beispiel 60 4-(1-Methylethyl)benzolsulfonylchlorid¹ 3,77 492 Beispiel 81 Beispiel 60 4-Chlorbenzolsulfonylchlorid¹ 3,64 484 Beispiel 82 Beispiel 60 2,4-Difluorbenzolsulfonylchlorid¹ 3,53 486 Beispiel 83 Beispiel 60 3-Chlorbenzolsulfonylchlorid¹ 3,65 484 Beispiel 84 Beispiel 60 5-Fluor-2-methylbenzolsulfonylchlorid¹ 3,65 482 Beispiel 85 Beispiel 60 3-Fluorbenzolsulfonylchlorid¹ 3,53 468 Beispiel 86 Beispiel 60 3-(Methyloxy)benzolsulfonylchlorid¹ 3,65 480 Beispiel 87 Beispiel 60 3,5-Difluorbenzolsulfonylchlorid¹ 3,73 486 Beispiel 88 Beispiel 60 3-Methylbenzolsulfonylchlorid² 3,71 464 Beispiel 89 Beispiel 60 4-(Methyloxy)benzolsulfonylchlorid² 3,35 416 Beispiel 90 Beispiel 60 1-Propansulfonylchlorid⁵ 3,39 416 Beispiel 91 Beispiel 60 Methansulfonylchlorid² 3,14 388 Beispiel 92 Beispiel 60 1-Butansulfonylchlorid¹ 3,46 430 Beispiel 93 Beispiel 60 1-Octansulfonylchlorid² 3,95 486 Beispiel 94 Beispiel 60 Cyclopropansulfonylchlorid³ 3,25 414 Beispiel 95 Beispiel 60 5-Chlor-2-thiophensulfonylchlorid¹ 3,68 490 Beispiel 96 Beispiel 60 3,5-Dimethyl-4-isoxazolsulfonylchlorid² 3,48 469 Beispiel 97 Beispiel 60 1,2-Dimethyl-1H-imidazol-4-sulfonylchlorid⁴ 3 468 Beispiel 98 Beispiel 60 Ethansulfonylchlorid² 3,21 402 Beispiel 99 Beispiel 60 2-Chlorbenzolsulfonylchlorid¹ 3,59 484 Beispiel 100 Beispiel 60 2-Methylbenzolsulfonylchlorid¹ 3,59 464 Beispiel 101 Beispiel 60 4-Ethylbenzolsulfonylchlorid⁴ 3,68 478 Beispiel 102 Beispiel 60 4-Propylbenzolsulfonylchlorid² 381 492 Beispiel 103 Beispiel 60 3,4-Difluorbenzolsulfonylchlorid¹ 3,59 486 Beispiel 104 Beispiel 60 4-Butylbenzolsulfonylchlorid² 3,9 506 Beispiel 105 Beispiel 60 Benzolsulfonylchlorid¹ 3,45 450 Beispiel 106 Beispiel 60 Phenylmethansulfonylchlorid¹ 3,42 464 Beispiel 107 Beispiel 60 (E)-2-Phenylethensulfonylchlorid¹ 3,58 476 Beispiel 108 Beispiel 60 2,5-Difluorbenzolsulfonylchlorid¹ 3,52 486 Beispiel 109 Beispiel 60 2-Fluorbenzolsulfonylchlorid¹ 3,47 468 Beispiel 110 Beispiel 60 4-Cyanobenzolsulfonylchlorid² 3,42 475 Beispiel 111 Beispiel 60 2,3-Dihydro-1-benzofuran-5-sulfonylchlorid⁴ 3,47 492

• ¹ Gekauft von Aldrich.
• ² Gekauft von Avocado.
• ³ Gekauft von Array Biopharma Inc.
• ⁴ Gekauft von Maybridge.
• ⁵ Gekauft von Pfaltz & Bauer.

Beispiel 112: N-Cyclopropyl-3-fluor-4-methyl-5-{1-[(4-methylphenyl)-sulfonyl]-1H-indol-5-yl}benzamid

A mixture of 1,1-dimethylethyl-5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazole-1-carboxylate (Example 59) (0.46 g) in a solution from hydrogen chloride in dioxane (4M, 7 mL) was stirred at room temperature under nitrogen for 4.5 h. The solvent was evaporated and the residue was partitioned between dichloromethane (20 ml) and aqueous sodium hydroxide (2M, 20 ml). The organic layer was separated using a hydrophobic filter tube, the solvent was evaporated, and the residue was passed through a Varian Bond Elut SPE cartridge (silica, 10 g) eluted with chloroform: methanol (100: 0 to 98: 2). , purified to give the title compound (0.06 g).
LC-MS: Rt 2.96 min, MH + 310. Example 61: N-Chloropropyl-4-methyl-3- {1 - [(1-methylethyl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 62: N-Chloropropyl-3- [1- (ethylsulfonyl) -1H-indazol-5-yl] -4-methylbenzamide

Prepared by General Procedure C. See Table. Example 63: N-Cyclopropyl-3- [1- (cyclopropylsulfonyl-1H-indazol-5-yl) -4-methylbenzamide

Prepared by General Procedure C. See Table. Example 64: Methyl 5 - [(5- {5 - [(cyclopropylamino) carbonyl] -2-methylpenyl} -1H-indazol-1-yl) sulfonyl] -2-furancarboxylate

Prepared by General Procedure C. See Table. Example 65: 3- [1- (2,1,3-Benzoxazol-4-ylsulfonyl) -1H-indazol-5-yl] -N-cyclopropyl-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 66: N-Cyclopropyl-3- {1 - [(2-fluoro-penyl) -sulfonyl] -1H-indazl-5-yl} -4-metylbenzamide

Prepared by General Procedure C. See Table. Example 67: N-Cyclopropyl-4-methyl-3- {1 - [(4-methylphenyl) sulfonyl] -1-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 68: N-Cyclopropyl-4-methyl-3- [1- (2-thienylsulfonyl) -1H-indazol-5-yl] benzamide

Prepared by General Procedure C. See Table. Example 69: N-Cyclopropyl-3- {1 - [(3,5-dimethyl-4-isoxazolyl) sulfonyl-1H-indazol-5-yl} -4-metylbenzamide

Prepared by General Procedure C. See Table. Example 70: N-Cylopropyl-4-methyl-3- [1- (propylsulfonyl) -1H-indazol-5-yl] benzamide

Prepared by General Procedure C. See Table. Example 71: N-Cyclopropyl-4-methyl-3- {1 - [(2-nitrophenyl) sulfonyl} -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 72: N-Cyclopropyl-4-methyl-3- {1 - [(2,2,2-trifluoroethyl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 73: 3- {1 - [(2-Cyanophenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 74: N-Cyclopropyl-4-methyl-3- {1 - [(1,3,5-trimethyl-1H-pyrazol-4-yl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 75: N-Cyclopropyl-4-methyl-3- {1- [1-methyl-1 H -imidazol-4-yl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 76: N-Cyclopropyl-3-fluoro-4-methyl-5- [1- (2-thienylsulfonyl) -1H-indazol-5-yl] benzamide

Prepared by General Procedure C. See Table. Example 77: N-Cyclopropyl-3-fluoro-4-methyl-5- [1- (3-thienylsulfonyl) -1H-indazol-5-yl] benzamide

Prepared by General Procedure C. See Table. Example 78: N-Cyclopropyl-3-fluoro-4-methyl-5- {1 - [(4-methylphenyl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 79: N-Cyclopropyl-3-fluoro-4-methyl-5- (1 - {[4- (methyloxy) -phenyl] sulfonyl} -1H-indazol-5-yl) -benzamide

Prepared by General Procedure C. See Table. Example 80: N-Cyclopropyl-3-fluoro-4-methyl-5- (1 - {[4- (1-methylethyl) phenyl] sulfonyl} -1H-indazol-5-yl) benzamide

Prepared by General Procedure C. See Table. Example 81: 3- {1 - [(4-Chlorophenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 82: N-Cyclopropyl-3- {1 - [(2,4-difluorophenyl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 83: 3- {1 - [(3-Chlorophenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 84: N-Cyclopropyl-3-fluoro-5- {1 - [(5-fluoro-2-methylphenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide

Prepared by General Procedure C. See Table. Example 85: N-Cyclopropyl-3-fluoro-5- {1 - [(3-fluorophenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide

Prepared by General Procedure C. See Table. Example 86: N-Cyclopropyl-3-fluoro-4-methyl-5- (1 - {[3- (methyloxy) -phenyl] sulfonyl} -1H-indazol-5-yl) -benzamide

Prepared by General Procedure C. See Table. Example 87: N-Cyclopropyl-3- {1 - [(3,5-difluorophenyl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 88: N-Cyclopropyl-3-fluoro-4-methyl-5- {1 - [(3-methylphenyl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 89: N-Cyclopropyl-3-fluoro-4-methyl-5- {1 - [(1-methylethyl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 90: N-Cyclopropyl-3-fluoro-4-methyl-5- [1- (propylsulfonyl) -1H-indazol-5-yl] benzamide

Prepared by General Procedure C. See Table. Example 91: N-Cyclopropyl-3-fluoro-4-methyl-5- [1- (methylsulfonyl) -1H-indazol-5-yl] benzamide

Prepared by General Procedure C. See Table. Example 92: 3- [1- (Butylsulfonyl) -1H-indazol-5-yl] -N-cyclopropyl-5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 93: N-Cyclopropyl-3-fluoro-4-methyl-5- [1- (octylsulfonyl) -1H-indazol-5-yl] benzamide

Prepared by General Procedure C. See Table. Example 94: N-Cyclopropyl-3- [1- (cyclopropylsulfonyl) -1H-indazol-5-yl] -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 95: 3- {1 - [(5-Chloro-2-thienyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 96: N-Cyclopropyl-3- {1 - [(3,5-dimethyl-4-isoxazolyl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 97: N-Cyclopropyl-3- {1 - [(1,2-dimethyl-1 H -imidazol-4-yl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 98: N-Cyclopropyl-3- [1- (ethylsulfonyl) -1H-indazol-5-yl] -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 99: 3- {1 - [(2-Chlorophenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 100: N-Cyclopropyl-3-fluoro-4-methyl-5- {1 - [(2-methylphenyl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 101: N-Cyclopropyl-3- {1 - [(4-ethylphenyl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 102: N-Cyclopropyl-3-fluoro-4-methyl-5- {1 - [(4-propylphenyl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 103: N-Cyclopropyl-3- {1- [3,4-difluorophenyl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 104: 3- {1 - [(4-Butylphenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 105: N-Cyclopropyl-3-fluoro-4-methyl-5- [1- (phenylsulfonyl) -1H-indazol-5-yl] benzamide

Prepared by General Procedure C. See Table. Example 106: N-Cyclopropyl-3-fluoro-4-methyl-5- {1 - [(phenylmethyl) sulfonyl] -1H-indazol-5-yl} benzamide

Prepared by General Procedure C. See Table. Example 107: N-Cyclopropyl-3-fluoro-4-methyl-5- (1 - {[(E) -2-phenylethenyl] sulfonyl} -1H-indazol-5-yl) benzamide

Prepared by General Procedure C. See Table. Example 108: N-Cyclopropyl-3- {1 - [(2,5-difluorophenyl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example 109: N-Cyclopropyl-3-fluoro-5- {1 - [(2-fluorophenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide

Prepared by General Procedure C. See Table. Example 110: 3- {1 - [(4-Cyanophenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Example III: N-Cyclopropyl-3- [1- (2,3-dihydro-1-benzofuran-5-ylsulfonyl) -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide

Prepared by General Procedure C. See Table. Table (Examples 61-111) Example no. Indazole precursor sulfonyl Rt (min) MH + Example 61 Example 17 2-propanesulfonyl chloride ¹ 3.17 398 Example 62 Example 17 Ethanesulfonyl chloride ² 3.13 384 Example 63 Example 17 cyclopropanesulfonyl chloride ³ 3.18 396 Example 64 Example 17 Methyl 5- (chlorosulfonyl) -2-furancarboxylate ⁴ 3.29 480 Example 65 Example 17 2,1,3-Benzoxadiazole-4-sulfonyl chloride ⁴ 3.36 474 Example 66 Example 17 2-fluorobenzenesulfonyl chloride ¹ 3.38 450 Example 67 Example 17 4-methylbenzenesulfonyl chloride ¹ 3.38 446 Example 68 Example 17 2-thiophenesulfonyl chloride ¹ 3.33 438 Example 69 Example 17 3,5-dimethyl-4-isoxazolesulfonyl chloride ⁴ 3.38 451 Example 70 Example 17 1-Propansulfonylchlorid5 3.11 398 Example 71 Example 17 2-nitrobenzenesulfonyl chloride ¹ 3.4 477 Example 72 Example 17 2,2,2-trifluoroethanesulfonyl chloride ¹ 3.11 438 Example 73 Example 17 2-cyanobenzenesulfonyl chloride ¹ 3.31 457 Example 74 Example 17 1,3,5-trimethyl-1H-pyrazol-4-sulfonyl chloride ⁴ 3.18 464 Example 75 Example 17 1-Methyl-1H-imidazole-4-sulfonyl chloride ⁴ 2.88 436 Example 76 Example 60 2-thiophenesulfonyl chloride ¹ 3.42 456 Example 77 Example 60 3-thiophenesulfonyl chloride ⁴ 3.39 456 Example 78 Example 60 4-methylbenzenesulfonyl chloride ¹ 3.57 464 Example 79 Example 60 4- (Methyloxy) benzenesulfonyl chloride ² 3.5 480 Example 80 Example 60 4- (1-Methylethyl) benzenesulfonyl chloride ¹ 3.77 492 Example 81 Example 60 4-chlorobenzenesulfonyl chloride ¹ 3.64 484 Example 82 Example 60 2,4-Difluorobenzenesulfonyl chloride ¹ 3.53 486 Example 83 Example 60 3-chlorobenzenesulfonyl chloride ¹ 3.65 484 Example 84 Example 60 5-Fluoro-2-methylbenzenesulfonyl chloride ¹ 3.65 482 Example 85 Example 60 3-fluorobenzenesulfonyl chloride ¹ 3.53 468 Example 86 Example 60 3- (Methyloxy) benzenesulfonyl chloride ¹ 3.65 480 Example 87 Example 60 3,5-Difluorobenzenesulfonyl chloride ¹ 3.73 486 Example 88 Example 60 3-methylbenzenesulfonyl chloride ² 3.71 464 Example 89 Example 60 4- (Methyloxy) benzenesulfonyl chloride ² 3,35 416 Example 90 Example 60 1-propanesulfonyl chloride ⁵ 3.39 416 Example 91 Example 60 Methanesulfonyl chloride ² 3.14 388 Example 92 Example 60 1-butanesulfonyl chloride ¹ 3.46 430 Example 93 Example 60 1-Octanesulfonyl chloride ² 3.95 486 Example 94 Example 60 Cyclopropanesulfonyl chloride ³ 3.25 414 Example 95 Example 60 5-chloro-2-thiophenesulfonyl chloride ¹ 3.68 490 Example 96 Example 60 3,5-dimethyl-4-isoxazolesulfonyl chloride ² 3.48 469 Example 97 Example 60 1,2-Dimethyl-1H-imidazole-4-sulfonyl chloride ⁴ 3 468 Example 98 Example 60 Ethanesulfonyl chloride ² 3.21 402 Example 99 Example 60 2-Chlorobenzenesulfonyl chloride ¹ 3.59 484 Example 100 Example 60 2-methylbenzenesulfonyl chloride ¹ 3.59 464 Example 101 Example 60 4-ethylbenzenesulfonyl chloride ⁴ 3.68 478 Example 102 Example 60 4-propylbenzenesulfonyl chloride ² 381 492 Example 103 Example 60 3,4-Difluorobenzenesulfonyl chloride ¹ 3.59 486 Example 104 Example 60 4-butylbenzenesulfonyl chloride ² 3.9 506 Example 105 Example 60 Benzenesulfonyl chloride ¹ 3.45 450 Example 106 Example 60 Phenylmethanesulfonyl chloride ¹ 3.42 464 Example 107 Example 60 (E) -2-Phenylethensulfonyl chloride ¹ 3.58 476 Example 108 Example 60 2,5-Difluorobenzenesulfonyl chloride ¹ 3.52 486 Example 109 Example 60 2-fluorobenzenesulfonyl chloride ¹ 3.47 468 Example 110 Example 60 4-cyanobenzenesulfonyl chloride ² 3.42 475 Example 111 Example 60 2,3-dihydro-1-benzofuran-5-sulfonyl chloride ⁴ 3.47 492

• ¹ Purchased by Aldrich.
• ² Bought of avocado.
• ³ Bought by Array Biopharma Inc.
• ⁴ Bought by Maybridge.
• ⁵ Purchased by Pfaltz & Bauer.

Example 112: N-Cyclopropyl-3-fluoro-4-methyl-5- {1 - [(4-methylphenyl) sulfonyl] -1H-indol-5-yl} benzamide

A mixture of 5-bromo-1 - [(4-methylphenyl) sulfonyl] -1H-indole (0.035 g), {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} boronic acid (interm. 64) (0.024g), saturated aqueous sodium bicarbonate (0.5ml) and tetrakis (triphenylphosphine) palladium (0) (2mg) in isopropanol (2ml) was heated in a microwave at 150 ° C for 10 minutes. The solid was removed by filtration and the residue was purified by preparative HPLC to give the title compound (0.013 g).
LC-MS: Rt 3.71 min, MH + 463. Example 113: N-Cyclopropyl-3-fluoro-4-methyl-5- [1- (phenylsulfonyl) -1H-indol-5-yl] -benzamide

The procedure for Example 112 was followed using 5-bromo-1- (phenylsulfonyl) -1H-indole (0.033 g) instead of 5-bromo-1 - [(4-methylphenyl) sulfonyl] -1H-indole to afford the To give the title compound (0.009 g).
LC-MS: Rt 3.61 min, MH + 449 Example 114: N-Cyclopropyl-3- [1- (cyclopropylmethyl) -1H-indazol-5-yl] -4-methylbenzamide

A solution of N-cyclopropyl-3- (1H-indazol-5-yl) -4-methylbenzamide (Example 17) (0.10g) in dry DMF (3ml) was treated with sodium hydride (60% oil dispersion, 0.017g ) under nitrogen. After 5 min, cyclopropylmethylbromide (0.04 mL) was added and the yellow solution was stirred at room temperature for 18 h. Methanol (2 drops) was added and the solvent was evaporated. The residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (2: 1 to 1: 1) to give the title compound (0.05 g).
LC-MS: Rt 3.21 min, MH + 346. Example 115: 1,1-Dimethylethyl-4- (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) -1-piperidinecarboxylate

A solution of N-cyclopropyl-3- (1H-indazol-5-yl) -4-methylbenzamide (Example 17) (0.07g) in dry DMF (3ml) was treated with sodium hydride (60% oil dispersion, 0.014g ) under nitrogen. After 5 minutes, 1,1-dimethylethyl 4 - [(methylsulfonyl) oxy] -1-piperidinecarboxylate (0.08 g) was added, and Mixture was stirred at room temperature for 18 h. 0.88 ammonia (1 ml) was added and the mixture was concentrated under vacuum. The residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (1: 1) followed by preparative reverse phase HPLC to give the title compound (0.005 g).
LC-MS: Rt 3.55 min, MH + 475. Example 116: N-Cyclopropyl-4-methyl-3- [1- (4-piperidinyl) -1H-indazol-5-yl] benzamide hydrochloride

A suspension of 1,1-dimethyl-4- (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) -1-piperidinecarboxylate (Example 115) (0.01 g) in a solution of hydrogen chloride in dioxane (4M, 1 mL) was treated with methanol (0.25 mL) to give a solution which was stirred at room temperature for 18 h. The solvent was evaporated and the residue was dried under vacuum to give the title compound (0.009 g).
LC-MS: Rt 2.40 min, MH + 375. Example 117. Methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate

A solution of N-cyclopropyl-3- (1H-indazol-5-yl) -4-methylbenzamide (Example 17) (0.65g) in dry DMF (26ml) was treated with sodium hydride (60% oil dispersion, 0.134g ) under nitrogen. After 5 min, methyl chloroacetate (0.29 g) was added and the mixture was stirred for 2 h. Aqueous ammonia (2M, 10 mL) was added and the solvent was removed in vacuo. The residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (2: 1 to 1: 1) to give the title compound (0.56 g).
LC-MS: Rt 2.95 min, MH + 364. Example 118: N-Cyclopropyl-3- (1H-indazol-6-yl) -4-methylbenzamide

A mixture of 1-acetyl-6-bromo-1H-indazole (intermediate 65) (0.50 g), N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) benzamide (interm. 5) (0.59 g), aqueous sodium Umhydrogencarbonate (1M, 2.35 mL) and PdCl ₂ dppf (0.237 g) in 1,2-dimethoxyethane (30 mL) were stirred at reflux under nitrogen for 16 h. More sodium carbonate (2.3 ml) and catalyst (120 mg) were added, and reflux was continued for a further 4 hours. Concentrated hydrochloric acid (1 ml) was added and the mixture was heated for an additional 1 hour. The mixture was absorbed on silica, then purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (2: 1 to 1: 4) to give the title compound (0.25 g).
LC-MS: Rt 2.88 min, MH + 292. Example 119: N-Cyclopropyl-3- {3 - [(4-fluorophenyl) sulfonyl] -1H-indazol-6-yl} -4-methylbenzamide

To a solution of N-cyclopropyl-3- [3 - [(4-fluorophenyl) sulfonyl] -1 - ({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indazol-6-yl] -4- methyl benzamide (Intermediate 71) (0.05 g) in methanol (1.5 ml) was added concentrated hydrochloric acid (0.75 ml). The solution was heated at reflux for 15 h, then left at room temperature for 18 h. The solution was concentrated under vacuum, then purified over a Varian Bond flood SPE cartridge (silica, 5 g) eluted with cyclohexane: ethyl acetate (1: 1) to give the title compound (0.01 g).
LC-MS: Rt 3.32 min, MH + 450. Example 120: N-Cyclopropyl-3-fluoro-4-methyl-5- [3- (methylsulfonyl) -1H-indazol-6-yl] -benzamide

Concentrated hydrochloric acid (0.5 ml) was added to a solution of N-cyclopropyl-3-fluoro-4-methyl-5- [3- (methylsulfonyl) -1 - ({[2- (trimethylsilyl) ethyl] oxy} methyl ) -1H-indazol-6-yl] benzamide (Intermediate 77) (0.15 g) and then stirred at reflux for 12 h. The solvent was evaporated and the residue was purified by column chromatography on silica eluted with cyclohexane: ethyl acetate (1: 1 to 1: 2) to give the title compound (0.085 g).
LC-MS: Rt 2.91 min, MH + 388. Example 121: N-Cyclopropyl-3-fluoro-4-methyl-5- (3-methyl-1H-indazol-5-yl) -benzamide

A mixture of 1-acetyl-5-bromo-3-methyl-1H-indazole (0.100 g), [5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} boronic acid (interm. 64) (0.094 g). saturated aqueous sodium bicarbonate (2ml) and tetrakis (triphenylphosphine) palladium (0) (9mg) in isopropanol (6ml) was heated in a microwave at 150 ° C for 10 minutes. The solvent was evaporated and the residue was purified on a Varian Bond Elut SPE cartridge (silica, 10 g), eluted with cyclohexane: ethyl acetate (1: 1), to give the title compound (0.073 g).
LC-MS: Rt 3.02 min, MH + 324. Example 122: N-Cyclopropyl-3-fluoro-4-methyl-5- [3-methyl-1- (2-thienylsulfonyl) -1H-indazol-5-yl ] benzamide

Sodium hydride (60% oil dispersion, 0.008 g) was added to a stirred solution of N-cyclopropyl-3-fluoro-4-methyl-5- (3-methyl-1H-indazol-5-yl) -benzamide (Example 121) (0.033 g) in dry DMF (1.5 ml) under nitrogen. After 5 minutes, a solution of 2-thiophenesulfonyl chloride (0.038 g) in DMF (0.75 ml) was added and stirring was continued for a further 2 hours. Water (1 ml) and chloroform (10 ml) were added, the mixture was passed through a hydrophobic filter, and the solvent was evaporated. The residue was purified by preparative HPLC to give the title compound as a clear glass (0.024 g).
LC-MS: Rt 3.44 min, MH + 470. Example 123: Methyl (5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate

A solution of N-cyclopropyl-3-fluoro-5- (1H-indazol-5-yl) -4-methylbenzamide (Example 60) (0.35g) in dry DMF (5ml) was treated with sodium hydride (60%) Oil dispersion, 0.08 g) at room temperature Treated with nitrogen, then stirred for 20 min. A solution of methyl bromoacetate (0.2 ml) in dry DMF (0.5 ml) was added and stirring was continued for 1 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (2x). The organic extracts were washed with water (3x) and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified using a Varian Bond flood SPE cartridge (silica, 10 g) eluted with cyclohexane: ethyl acetate (4: 1 to 1: 1) to afford the title compound as a yellow foam (0.26 g ).
LC-MS: Rt 3.03 min, MH + 382. Example 124: N-Cyclopropyl-4-methyl-3- {1- [2- ({4- (methyloxy) -phenyl] -methyl} -amino) -2-oxo-ethyl ] -1H-indazol-5-yl} benzamide

Example 124 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) and 4-methoxybenzylamine, to give the title compound (0.011 g).
LC-MS: Rt 2.99 min, MH + 469. Example 125: N-Cyclopropyl-4-methyl-3- (1- {2-oxo-2 - [(phenylmethyl) amino] ethyl} -1H-indazole-5 -yl) benzamide

Example 125 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) and benzylamine to obtain the To give the title compound (0.002 g).
LC-MS: Rt 3.00 min, MH + 439. Example 126: N-Cyclopropyl-4-methyl-3- [1- (2 - {[4-methylphenyl) methyl] amino} -2-oxoethyl) -1H-indazol-5-yl] benzamide

Example 126 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) and 4-methylbenzylamine, to give the title compound (0.010 g).
LC-MS: Rt 3.11 min, MH + 453. Example 127: N-Cyclopropyl-4-methyl-3- (1- {2 - [({4 - [(methylamino) carbonyl] phenyl} methyl) amino] - 2-oxoethyl} -1H-indazol-5-yl) benzamide

Example 127 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) and 4- (aminomethyl) N-methylbenzamide to give the title compound (0.005 g).
LC-MS: Rt 2.68 min, MH + 496. Example 128: N-Cyclopropyl-4-methyl-3- {1- [2-oxo-2- (propylamino) ethyl] -1H-indazol-5-yl } benzamide

Example 128 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) and 1-propylamine, around to give the title compound (0.011 g).
LC-MS: Rt 2.81 min, MH + 391. Example 129: N-Cyclopropyl-3- (1- {2 - [(cyclopropylmethyl) amino] -2-oxo-ethyl} -1H-indazol-5-yl) -4-methylbenzamide

Example 129 was prepared by General Procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) and 1-cyclopropylmethanamine, to give the title compound (0.015 g).
LC-MS: Rt 2.86 min, MH + 403. Example 130: N-Cyclopropyl-3- (1- {2 - [(2,2-dimethylpropyl) amino] -2-oxoethyl} -1H-indazole-5- yl) -4-methylbenzamide

Example 130 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) and 2,2-dimethyl 1-propanamine to give the title compound (0.015 g).
LC-MS: Rt 3.06 min, MH + 419. Example 131: N-Cyclopropyl-4-methyl-3- {1- [2- (4-morpholinyl) -2-oxoethyl] -1H-indazol-5-yl } benzamide

Example 131 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) and morpholine to obtain the To give the title compound (0.002 g).
LC-MS: Rt 2.66 min, MH + 419. Example 132: N-Cyclopropyl-3-fluoro-4-methyl-5- (1- {2-oxo-2 - [(phenylmethyl) amino] ethyl} -1H -indazole-5-yl) benzamide

Example 132 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate (Example 123) and benzylamine to give the title compound (0.008 g).
LC-MS: Rt 3.17 min, MH + 457. Example 133: N-Cyclopropyl-3-fluoro-4-methyl-5- [1- (2 - {[(4-methylphenyl) methyl] amino} -2- oxoethyl) -1H-indazol-5-yl] benzamide

Example 133 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate (Example 123) and 4 -Methylbenzylamine prepared to give the title compound (0.011 g).
LC-MS: Rt 3.28 min, MH + 471. Example 134: N-Cyclopropyl-3-fluoro-4-methyl-5- {1- [2- ({[4- (methyloxy) phenyl] methyl} amino) -2-oxoethyl] -1H-indazol-5-yl } benzamide

Example 134 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate (Example 123) and 4 -Methoxybenzylamine prepared to give the title compound (0.012 g).
LC-MS: Rt 3.15 min, MH + 487. Example 135: N-Cyclopropyl-3-fluoro-4-methyl-5- (1- {2 - [({4 - [(methylamino) carbonyl] phenyl} methyl ) amino] -2-oxoethyl} -1H-indazol-5-yl) benzamide

Example 135 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate (Example 123) and 4 - (Aminomethyl) -N-methylbenzamide to give the title compound (0.005 g).
LC-MS: Rt 2.80 min, MH + 514. Example 136: N-Cyclopropyl-3-fluoro-4-methyl-5- {1- [2-oxo-2- (propylamino) ethyl] -1H-indazole 5-yl} benzamide

Example 136 was prepared by general procedure D using methyl (5- {5 - [(cyclopro pylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate (Example 123) and 1-propylamine to afford the title compound (0.005 g).
LC-MS: Rt 2.92 min, MH + 409. Example 137: N-Cyclopropyl-3- (1- {2 - [(cyclopropylmethyl) amino] -2-oxoethyl} -1H-indazol-5-yl) -5 -fluoro-4-methylbenzamide

Example 137 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate (Example 123) and 1 -Cyclopropylmethanamine to give the title compound (0.008 g).
LC-MS: Rt 2.96 min, MH + 421. Example 138: N-Cyclopropyl-3-fluoro-4-methyl-5- {1- [2- (4-morpholinyl) -2-oxoethyl] -1H-indazole -5-yl} benzamide

Example 138 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate (Example 123) and morpholine to give the title compound (0.001 g).
LC-MS: Rt 2.76 min, MH + 437. Example 139: N-Cyclopropyl-4-methyl-3- (1- {2 - [(1-methylethyl) amino] -2-oxoethyl} -1H-indazole 5-yl) benzamide

Example 139 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -2-methylphenyl} -1H-indazol-1-yl) acetate (Example 117) and 2-propylamine, to give the title compound (0.002 g).
LC-MS: Rt 2.82 min, MH + 391. Example 140: N-Cyclopropyl-3- (1- {2 - [(2,2-dimethylpropyl) amino] -2-oxoethyl} -1H-indazole-5- yl) -5-fluoro-4-methylbenzamide

Example 140 was prepared by general procedure D using methyl (5- {5 - [(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -1H-indazol-1-yl) acetate (Example 123) and 2 , 2-Dimethyl-1-propanamine to give the title compound (0.008 g).
LC-MS: Rt 3.21 min, MH + 437. Example 141: N-Cyclopropyl-3- {2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} -4-methylbenzamide

Example 141 was prepared by general procedure A using N- (6-bromo-1,3-benzothiazol-2-yl) cyclopropanecarboxamide and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) benzamide (Intermediate 5) to give the title compound (0.4 g).
LC-MS: Rt 2.67 min, MH + 392.

Abbreviations:

Ac ₂ O

acetic anhydride

^t BuONO

t-Butyl nitrite

CDI

carbonyldiimidazole

DBU

1,8-diazabicyclo [5.4.0] undec-7-ene

DIPEA

N, N-diisopropylethylamine

DME

1,2-dimethoxyethane

DMF

dimethylformamide

DMSO

dimethyl sulfoxide

Et ₂ O

ether

EtOH

ethanol

Hal

halogen

HATU

0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium

HOBT

1-hydroxybenzotriazole

KOAc

potassium acetate

MeCN

acetonitrile

MeOH

methanol

ms

mesyl

NaO ^t Bu

Sodium tert-butoxide

NaOEt

sodium

NCS

N-chlorosuccinimide

PdCl ₂ dppf

[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -

complex

with dichloromethane (1: 1)

Rt

Retention time (retention time)

SPE

Solid Phase Extraction (solid phase extraction)

THF

tetrahydrofuran

Biological examples

The activity The compounds of formula (I) as p38 inhibitors can by the following in vitro tests are determined:

Kinase binding assay by Fluoreszenzanisotrophie

The Kinase enzyme, fluorescent ligand and a variable concentration of Test compound are incubated together to form a thermodynamic Achieve equilibrium under conditions in which absence The test compound of the fluorescent ligand was significantly (> 50%) enzyme bound and in the presence of a sufficient concentration (> 10 x Ki) of a potential inhibitor the anisotropy of the unbound fluorescent ligand measurably different of the bound value.

The concentration of the kinase enzyme should preferably be> 1 × K _f . The concentration of the fluorescent ligand required depends on the instrumentation used and the fluorescence and physicochemical properties. The concentration used must be lower than the concentration of the kinase enzyme, and preferably less than half of the kinase enzyme concentration. A typical protocol is: All components dissolved in buffer with the final composition 62.5 mM HEPES, pH 7.5, 1.25 mM CHAPS, 1.25 mM DTT, 12.5 mM MgCl ₂ , 3.3% DMSO.
p38 enzyme concentration: 12 nM
Fluorescence ligand concentration: 5 nM
Test compound concentration: 0.1 nM-100 μM

The Components are dissolved in 30 μl Final volume in NUNC 384 black hole microtiter plates until equilibrium is reached (5-30 min) incubated.

K_i

= Dissoziationskonstante der Inhibitorbindung

K_f

= Dissoziationskonstante der Fluoreszenzligandenbindung.

Fluorescence anisotropy measured in LJL Acquest. definitions:

K _i

= Dissociation constant of inhibitor binding

K _f

= Dissociation constant of fluorescence ligand binding.

die abgeleitet ist von 5-[2-(4-Aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorphenol und Rhodamingrün.The fluorescence ligand is the following compound:

which is derived from 5- [2- (4-aminomethylphenyl) -5-pyridin-4-yl-1H-imidazol-4-yl] -2-chlorophenol and rhodamine green.

Results

The compounds described in the Examples were tested as described above and had IC ₅₀ values of <10 μM.

Claims (11)

Compound of the formula (I):

wherein: A is a fused 5-membered heteroaryl ring which is optionally substituted with up to two substituents independently selected from C _1-6 alkyl, - (CH _{2) m} -C _3-7 cycloalkyl, halogen, cyano , Trifluoromethyl, - (CH ₂ ) _m OR ³ , - (CH ₂ ) _m CO ₂ R ³ , - (CH ₂ ) _m NR ³ R ⁴ , - (CH ₂ ) _m CONR ³ R ⁴ , - (CH ₂ ) _m NHCOR ³ , - (CH ₂ ) _m SO ₂ NR ³ R ⁴ , - (CH ₂ ) _m NHSO ₂ R ³ , - (CH ₂ ) _m SO ₂ (CH ₂ ) _n R ⁵ , a 5- or 6- heterocyclyl heterocyclic ring containing nitrogen optionally substituted with C _1-2 alkyl or - (CH ₂ ) _m CO ₂ R ³ and a 5-membered heteroaryl ring optionally substituted with C _1-2 alkyl; R ^{1 is} selected from methyl and chloro; R ^{2 is} selected from -NH-CO-R ⁶ and -CO-NH- (CH ₂ ) _q -R ⁷ ; R ^{3 is} selected from hydrogen, C _1-6 alkyl optionally substituted with up to two OH groups, - (CH ₂ ) _m -C _3-7 cycloalkyl, - (CH ₂ ) _m phenyl optionally substituted with R ⁸ and / or R ⁹ , and - (CH ₂ ) _m heteroaryl, which is optionally substituted with R ⁸ and / or R ⁹ ; R ^{4 is} selected from hydrogen and C _1-6 alkyl, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally containing an additional heteroatom which selected from oxygen, sulfur and NR ¹⁰ ; R ^{5 is} selected from C _1-6 alkyl optionally substituted with up to three halogen atoms, C _2-6 alkenyl optionally substituted with phenyl, C _3-7 cycloalkyl, heteroaryl optionally substituted with up to three R ⁸ and / or R ⁹ groups is substituted, and phenyl which is optionally substituted with R ⁸ and / or R ⁹ ; R ⁶ is selected from hydrogen, C _1-6 alkyl, - (CH _{2) q} -C _3-7 ^- cycloalkyl, trifluoromethyl, - (CH _{2) r} heteroaryl optionally substituted by R ¹¹ and / or R ¹² and - (CH ₂ ) _r phenyl optionally substituted with R ¹¹ and / or R ¹² ; R ^{7 is} selected from hydrogen, C _1-6 -alkyl, C _3-7 -cycloalkyl, -CONHR ¹³ , phenyl optionally substituted with R ¹¹ and / or R ¹² , and heteroaryl optionally substituted with R ¹¹ and / or R ^{12 is} substituted; R ⁸ and R ^{9 are} each independently selected from halo, cyano, trifluoromethyl, nitro, C _1-6 alkyl, C _1-6 alkoxy, -CONR ¹³ R ¹⁴ , -COR ¹⁵ , -CO ₂ R ¹⁵ and heteroaryl, or R ⁸ and R ^{9 are} linked to form a fused 5-membered heterocyclyl ring containing a heteroatom selected from oxygen, sulfur and NR ¹⁰ , or a fused heteroaryl ring; R _{10 is} selected from hydrogen and methyl; R ¹¹ is selected from C _1-6 alkyl, C _1-6 alkoxy, - (CH _{2) q} -C _3-7 ^- cycloalkyl, -CONR ¹³ R ^14, -NHCOR ^14, halogen, CN, - (CH ₂ ) _s NR ¹⁶ R ¹⁷ , trifluoromethyl, phenyl optionally substituted with one or more R ¹² groups, and heteroaryl optionally substituted with one or more R ¹² groups; R ^{12 is} selected from C _1-6 alkyl, C _1-6 alkoxy, halo, trifluoromethyl and - (CH ₂ ) _s NR ¹⁶ R ¹⁷ ; R ¹³ and R ^{14 are} each independently selected from hydrogen and C _1-6 alkyl, or R ¹³ and R ^14, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring optionally containing an additional heteroatom selected from oxygen, sulfur and NR ¹⁰ wherein the ring is substituted with bis may be substituted alkyl groups ^- to two C _1-6; R ^{15 is} C _1-6 alkyl; R ¹⁶ is selected from hydrogen, C _1-6 alkyl and - (CH _{2) q} -C _3-7 ^- cycloalkyl, which is optionally substituted with C _1-6 alkyl; R ^{17 is} selected from hydrogen and C _1-6 alkyl, or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally containing an additional heteroatom which is selected from oxygen, sulfur and NR ¹⁰ ; X and Y are each independently selected from hydrogen, methyl and halogen; m is selected from 0, 1, 2 and 3; n is selected from 0, 1, 2 and 3; q is selected from 0, 1 and 2; r is selected from 0 and 1; and s is selected from 0, 1, 2 and 3; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 1, wherein A is a fused 5-membered heteroaryl ring containing up to two heteroatoms independently selected from oxygen and nitrogen optionally substituted with up to two substituents independently selected from C _1-4 alkyl , - (CH ₂ ) _m -C _3-7 -cycloalkyl, - (CH ₂ ) _m CO ₂ R ³ , - (CH ₂ ) _m NR ³ R ⁴ , - (CH ₂ ) _m CONR ³ R ⁴ , - ( CH ₂ ) _m NHCOR ³ , - (CH ₂ ) _m SO ₂ (CH ₂ ) _n R ⁵ and a 5- or 6-membered heterocyclyl ring containing nitrogen optionally substituted with C _1-2 alkyl or - (CH ₂ ) _m CO ₂ R ^{3 is} substituted. A compound according to claim 1 or 2, wherein R ^{1 is} methyl. A compound according to any one of the preceding claims wherein R ^{2 is} -CO-NH- (CH ₂ ) _q -R ⁷ . Connection according to one of the preceding claims, wherein X is hydrogen or fluorine. A compound according to claim 1, which is: N- [4-methyl-3- (3-piperidin-4-yl-1,2-benzisoxazol-6-yl) phenyl] -2-pyrrolidin-1-ylisonicotinamide, N- Cyclopropyl 4-methyl-3- [1- (phenylsulfonyl) -1H-indazol-5-yl] benzamide, N-cyclopropyl-3- {1 - [(3-fluorophenyl) sulfonyl] -1H-indazol-5-yl } -4-methylbenzamide, N-cyclopropyl-4-methyl-3- [1- (methylsulfonyl) -1H-indazol-5-yl] -benzamide, N-cyclopropyl-3- {1 - [(4-fluorophenyl) sulfonyl ] -1H-indazol-5-yl} -4-methylbenzamide, N-cyclopropyl-4-methyl-3- [3- (4-morpholinyl) -1,2-benzisoxazol-6-yl] benzamide, N-cyclopropyl 4-methyl-3- {3- [2-oxo-2- (1,3-thiazol-2-ylamino) ethyl] -1,2-benzisoxazol-6-yl} benzamide, N-cyclopropyl-4-methyl 3- [3- (4-morpholinylmethyl) -1,2-benzisoxazol-6-yl] benzamide, N-cyclopropyl-4-methyl-3- [3- (1-pyrrolidinylmethyl) -1,2-benzisoxazole-6- yl] benzamide, N-cyclopropyl-4-methyl-3- {1 - [(1-methylethyl) sulfonyl] -1H-indazol-5-yl} benzamide, N-cyclopropyl-3- [1- (ethylsulfonyl) -1H -indazol-5-yl] -4-methylbenzamide, N-cyclopropyl-3- [1- (cyclopropylsulfonyl) -1H-indazol-5-yl] -4-me ethylbenzamide, N-cyclopropyl-4-methyl-3- [1- (2-thienylsulfonyl) -1H-indazol-5-yl] benzamide, 3- {1 - [(2-cyanophenyl) sulfonyl] -1H-indazole-5 -yl} -N-cyclopropyl-4-methylbenzamide, N-cyclopropyl-3-fluoro-4-methyl-5- [1- (2-thienylsulfonyl) -1H-indazol-5-yl] benzamide, N-cyclopropyl-3 fluoro-4-methyl-5- [1- (3-thienylsulfonyl) -1H-indazol-5-yl] benzamide, N-cyclopropyl-3-fluoro-4-methyl-5- {1 - [(1-methylethyl ) sulfonyl] -1H-indazol-5-yl} benzamide, N-cyclopropyl-3-fluoro-4-methyl-5- [1- (propylsulfonyl) -1H-indazol-5-yl] -benzamide, N-cyclopropyl-3 fluoro-4-methyl-5- [1- (methylsulfonyl) -1H-indazol-5-yl] benzamide, 3- [1- (butylsulfonyl) -1H-indazol-5-yl] -N-cyclopropyl-5- fluoro-4-methylbenzamide, N-cyclopropyl-3- [1- (cyclopropylsulfonyl) -1H-indazol-5-yl] -5-fluoro-4-methylbenzamide, 3- {1 - [(5-chloro-2-thienyl ) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide, N-cyclopropyl-3- {1 - [(3,5-dimethyl-4-isoxazolyl) sulfonyl] -1H -indazol-5-yl} -5-fluoro-4-methylbenzamide, N-cyclopropyl-3- [1- (ethylsulfonyl) -1H-indazol-5-yl] -5-fluoro-4-methyl benzamide, 3- {1 - [(2-chlorophenyl) sulfonyl] -1H-indazol-5-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide, N-cyclopropyl-3-fluoro-4-methyl-5 - {1 - [(2-methylphenyl) sulfonyl] -1H-indazol-5-yl} benzamide, N-cyclopropyl-3-fluoro-4-methyl-5- [1- (phenylsulfonyl) -1H-indazole-5- yl] benzamide, N-cyclopropyl-3- {1 - [(2,5-difluorophenyl) sulfonyl] -1H-indazol-5-yl} -5-fluoro-4-methylbenzamide, N-cyclopropyl-3-fluoro-5 - {1 - [(2-fluorophenyl) sulfonyl] -1H-indazol-5-yl} -4-methylbenzamide, N-cyclopropyl-3- [1- (cyclopropylmethyl) -1H-indazol-5-yl] -4-methylbenzamide and N-cyclopropyl-3-fluoro-4-methyl-5- [3-methyl-1- (2- thienylsulfonyl) -1H-indazol-5-yl] benzamide, or a pharmaceutically acceptable salt or solvate thereof. Pharmaceutical composition containing a compound according to one the claims 1 to 6 or a pharmaceutically acceptable salt thereof in the mixture with one or more pharmaceutically acceptable carriers, diluents or excipients. Connection according to one the claims 1 to 6 or a pharmaceutically acceptable salt or solvate thereof for use in therapy. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in the treatment of a Condition or disease condition caused by p38 kinase activity or by Cytokines caused by the activity p38 kinase are produced. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or solvate thereof which comprises the steps of: (a) reacting a compound of formula (II):

wherein A is as defined in claim 1 and Z ^{1 is} halogen, with a compound of formula (IIIA) or (IIIB):

wherein R ¹ , R ² , X and Y are as defined in claim 1, in the presence of a catalyst, or (b) final stage modification of a compound of formula (I) as defined in claim 1 to another compound of formula (I) as defined in claim 1. A compound according to claim 1 wherein the compound is that of formula (IA):

wherein: A is a fused 5-membered heteroaryl ring optionally substituted with up to two substituents independently selected from C _1-6 alkyl, - (CH ₂ ) _m -C _3-7 cycloalkyl, halo, cyano , Trifluoromethyl, - (CH ₂ ) _m OR ³ , - (CH ₂ ) _m NR ³ R ⁴ , - (CH ₂ ) _m CONR ³ R ⁴ , - (CH ₂ ) _m NHCOR ³ , - (CH ₂ ) _m SO ₂ NR ³ R ⁴ , - (CH ₂ ) _m NHSO ₂ R ³ , - (CH ₂ ) _m SO ₂ (CH ₂ ) _n R ⁵ , a 5- or 6-membered heterocyclyl ring containing nitrogen optionally substituted with C _1-2 alkyl, and a 5-membered heteroaryl ring optionally substituted with C _1-2 alkyl; R ^{1 is} selected from methyl and chloro; R ^{2 is} selected from -NH-CO-R ⁶ and -CO-NH- (CH ₂ ) _q -R ⁷ ; R ^{3 is} selected from hydrogen, C _1-6 alkyl optionally substituted with up to two OH groups, - (CH ₂ ) _m -C _3-7 cycloalkyl, - (CH ₂ ) _m phenyl optionally substituted with R ⁸ and / or R ⁹ , and - (CH ₂ ) _m heteroaryl, which is optionally substituted with R ⁸ and / or R ⁹ ; R ^{4 is} selected from hydrogen and C _1-6 alkyl, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally containing an additional heteroatom which is selected from oxygen, sulfur and NR ¹⁰ ; R ^{5 is} selected from C _1-6 alkyl, C _3-7 cycloalkyl, heteroaryl optionally substituted with R ⁸ and / or R ⁹ , and phenyl optionally substituted with R ⁸ and / or R ⁹ ; R ⁶ is selected from hydrogen, C _1-6 alkyl, - (CH _{2) q} -C _3-7 ^- cycloalkyl, trifluoromethyl, - (CH _{2) r} heteroaryl optionally substituted by R ¹¹ and / or R ¹² and - (CH ₂ ) _r phenyl optionally substituted with R ¹¹ and / or R ¹² ; R ^{7 is} selected from hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, CONHR ¹³ , phenyl optionally substituted with R ¹¹ and / or R ¹² , and heteroaryl optionally substituted with R ¹¹ and / or R ^{12 is} substituted; R ⁸ and R ^{9 are} each independently selected from halogen, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, COR ¹⁵ , CO ₂ R ¹⁵ and heteroaryl, or R ⁸ and R ^{9 are} linked to to form a fused 5-membered heterocyclyl ring containing a heteroatom selected from oxygen, sulfur and NR ¹⁰ ; R ^{10 is} selected from hydrogen and methyl; R ¹¹ is selected from C _1-6 alkyl, C _1-6 alkoxy, - (CH _{2) q} -C _3-7 ^- cycloalkyl, -CONR ¹³ R ^14, -NHCOR ^14, halogen, CN, - (CH ₂ ) _s NR ¹⁶ R ¹⁷ , trifluoromethyl, phenyl optionally substituted with one or more R ¹² groups, and heteroaryl optionally substituted with one or more R ¹² groups; R ¹² is selected from C _1-6 alkyl, C ₁ _ ₅ alkoxy, halogen, trifluoromethyl and - (CH _{2) s} NR ¹⁶ R ^17; R ¹³ and R ^{14 are} each independently selected from hydrogen and C _1-6 alkyl, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally containing one containing additional heteroatom selected from oxygen, sulfur and NR ¹⁰ wherein the ring may be substituted with up to two C _1-6 alkyl groups; R ^{15 is} C _1-6 alkyl; R ¹⁶ is selected from hydrogen, C _1-6 alkyl and - (CH _{2) q} -C _3-7 cycloalkyl, which is substituted by C _1-6 alkyl optionally substituted R ¹⁷ is selected from hydrogen and C _{1- 6} -alkyl, or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally containing an additional heteroatom selected from oxygen, sulfur and NR ¹⁰ ; m is selected from 0, 1, 2 and 3; n is selected from 0, 1, 2 and 3; q is selected from 0, 1 and 2; r is selected from 0 and 1; and s is selected from 0, 1, 2 and 3; or a pharmaceutically acceptable salt or solvate thereof.